The present invention relates to novel pyrimidine derivatives and to the use of such derivatives and related compounds to inhibit sorbitol dehydrogenase (SDH), lower fructose levels, or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. This invention also relates to pharmaceutical compositions containing such pyrimidine derivatives and related compounds. This invention also relates to pharmaceutical compositions comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an aldose reductase inhibitor and to the use of such compositions to treat or prevent diabetic complications in mammals. This invention also relates to pharmaceutical compositions comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an NHE-1 inhibitor and to the use of such compositions to reduce tissue damage resulting from ischemia, and particularly to prevent perioperative myocardial ischemic injury.
S. Ao et al., Metabolism, 40, 77-87 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates more closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A (1991). In both of these cases, lowering of nerve fructose was achieved using relatively high does of aldose reductase inhibitors, which inhibit the formation of sorbitol, a precursor of fructose, from glucose via the enzyme aldose reductase.
U.S. Pat. Nos. 5,138,058 and 5,215,990, which are hereby incorporated by reference, each disclose compounds of the formula 
where R1, R2, R3, R4 and R5 are as disclosed therein. Said compounds are disclosed as having utility as tools in screening for aldose reductase inhibitors due to the sorbitol accumulating activity of said compounds.
Commonly assigned U.S. Pat. Nos. 5,728,704 and 5,866,578, which are hereby incorporated by reference, each disclose compounds of the formula A, 
wherein R1 through R5 are defined as disclosed therein. Further, U.S. Pat. No. 5,728,704 discloses that sorbitol dehydrogenase compounds have utility in the treatment of diabetic complications.
Pyrimidine derivatives of the formula I, as defined below, and their pharmaceutically acceptable salts, lower fructose levels in the tissues of mammals affected by diabetes (e.g., nerve, kidney and retina tissue) and are useful in the treatment and prevention of the diabetic complications referred to above. These compounds, or their metabolites in vivo, are inhibitors of the enzyme sorbitol dehydrogenase, which catalyzes the oxidation of sorbitol to fructose.
The present invention is directed to a compound of the formula I 
a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
R1 is formyl, acetyl, propionyl, carbamoyl or xe2x80x94C(OH)R4R5;
R4 and R5 are each independently hydrogen, methyl, ethyl or hydroxy-(C1-C3)alkyl;
R2 is hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy;
R3 is a radical of the formula 
xe2x80x83wherein said radical of formula R3a is additionally substituted on the ring by R6, R7 and R8;
said radical of formula R3b is additionally substituted on the ring by R18, R19 and R20; G, G1 and G2 are taken separately and are each hydrogen and R6 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the-definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; R7 and R8 are each independently hydrogen or (C1-C4)alkyl; or
G and G1 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G2 are hydrogen; or
G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G are hydrogen;
q is 0 or 1;
X is a covalent bond, xe2x80x94(Cxe2x95x90NR10)xe2x80x94, oxycarbonyl, vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl, thio(C1-C4)alkylenylcarbonyl, vinylenylsulfonyl, sulfinyl-(C1-C4)alkylenylcarbonyl, sulfonyl-(C1-C4)alkylenylcarbonyl or carbonyl(C0-C4)alkylenylcarbonyl; wherein said oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl and thio(C1-C4)alkylenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C1-C4)alkyl, benzyl or Ar; said vinylenylsulfonyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar; and said carbonyl(C0-C4)alkylenylcarbonyl in the definition of X is optionally substituted independently with up to three (C1-C4)alkyl, benzyl or Ar;
R10 is hydrogen or (C1-C4)alkyl;
R9 is (C3-C7)cycloalkyl, Ar1xe2x80x94(C0-C3)alkylenyl or (C1-C6)alkyl optionally substituted with up to five fluoro; provided that when q=0 and X is a covalent bond, oxycarbonyl or (C1-C4)alkylenylcarbonyl, then R9 is not (C1-C6)alkyl;
Ar and Ar1 are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five- to seven-membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocyclic ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
Ar and Ar1 are optionally independently substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to a total of four substituents independently selected from R11, R12, R13 and R14; wherein R11, R12, R13 and R14 are each taken separately and are each independently halo, formyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, C(OH)R15R16, naphthyl, phenyl, imidazolyl, pyridyl, triazolyl, morpholinyl, (C0-C4)alkylsulfamoyl, N-(C0-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, N-phenylcarbamoyl, N-(C1-C4)alkyl-N-phenylcarbamoyl, N,N-diphenyl carbamoyl, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, 8-(C1-C4)alkyl-3,8-diaza[3.2.1]bicyclooctyl, 3,5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfonyl, (C3-C7)cycloalkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl, thienyl, benzothiazolyl, pyrrolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the definition of R11, R12, R13 and R14 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of R11, R12, R13 and R14 are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from (C1-C4)alkyl; said pyrrolidinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from hydroxy, hydroxy-(C1-C3)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to three substituents independently selected from (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, (C0-C4)alkylsulfamoyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said triazolyl in the definition of R11, R12, R13 and R14 is optionally substituted with hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said tetrazolyl in the definition of R11, R12, R13 and R14 is optionally substituted with hydroxy-(C2-C3)alkyl or (C1-C4)alkyl optionally substituted with up to five fluoro; and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R11, R12, R13 and R14 are optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R11 and R12 are taken together on adjacent carbon atoms and are xe2x80x94CH2OC(CH3)2OCH2xe2x80x94 or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94, and R13 and R14 are taken separately and are each independently hydrogen or (C1-C4)alkyl;
p is 1, 2 or 3;
R15 and R16 are taken separately and are each independently hydrogen, (C1-C4)alkyl optionally substituted with up to five fluoro; or R15 and R16 are taken separately and R15 is hydrogen and R16 is (C3-C6)cycloalkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or benzoxazolyl; or R15 and R16 are taken together and are (C3-C6)alkylene;
G3, G4 and G5 are taken separately and are each hydrogen; r is 0; R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; and R19 and R20 are each independently (C1-C4)alkyl; or
G3, G4 and G5 are taken separately and are each hydrogen; r is 1; R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; and R19 and R20 are each independently hydrogen or (C1-C4)alkyl; or
G3 and G4 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G5 are hydrogen; or
G4 and G5 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G3 are hydrogen;
R17 is SO2NR21R22, CONR21R22, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, Ar2-carbonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, Ar2-sulfonyl, Ar2-sufinyl and (C1-C6)alkyl;
R21 and R22 are taken separately and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl and Ar2xe2x80x94(C0-C4)alkylenyl; or
R21 and R22 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-isoquinolyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R21 and R22 is optionally substituted independently with one substituent selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl, azepinyl in the definition of R21 and R22 are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R21 and R22 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of R21 and R22 is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl, (C1-C4)alkoxycarbonyl and (C1-C4)alkyl optionally substituted with up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R21 and R22 are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R21 and R22 is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrimidyl, pyridyl and phenyl which are optionally substituted on said piperazine in the definition of R21 and R22 is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
Ar2 is independently defined as set forth for Ar and Ar1 above;
said Ar2 is optionally independently substituted as set forth for Ar and Ar1 above;
R23 is CONR25R26 or SO2R25R26, wherein R25 is hydrogen (C1-C4)alkyl or Ar3xe2x80x94(C0-C4)alkylenyl and R26 is Ar3xe2x80x94(C0-C4)alkylenyl; provided that when Ar3 is phenyl, naphthyl or biphenyl, then RF cannot be CONR25R26 where R25 is hydrogen or Ar3 and R26 is Ar3;
R24 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro;
Ar3 is independently defined as set forth for Ar and Ar1 above;
said Ar3 is optionally independently substituted as set forth for Ar and Ar1 above;
R27 is hydrogen or (C1-C4)alkyl;
R28 and R29 are each independently hydrogen, hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro, (C1-C4)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, SO2NR30R31, CONR30R31 or NR30R31; said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R28 and R29 are optionally substituted by up to two hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R28 and R29 are optionally substituted by up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R30 and R31 are each independently hydrogen, (C1-C4)alkyl, (C3-C7)cycloalkyl or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R30 and R31 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyl in the definition of R30 and R31 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R30 and R31 are optionally substituted with up to three hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R30 and R31 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C1-C4)alkyl and B is carbonyl; or
A is carbonyl and B is N optionally substituted with hydrogen or (C1-C4)alkyl;
R32 is hydrogen or (C1-C4)alkyl;
R33 is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl or benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R33 are optionally substituted with up to three phenyl, phenoxy, NR34R35, halo, hydroxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R34 and R35 are each independently hydrogen, (C1-C4 alkyl), phenyl or phenylsulfonyl;
said phenyl and phenylsulfonyl in the definition of R34 and R35 are optionally substituted with up to three halo, hydroxy, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
D is CO, CHOH or CH2;
E is O, NH or S;
R36 and R37 are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, pyrrolidino, piperidino, morpholino, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl, Ar4, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R38, R39 and R40 are each independently hydrogen or (C1-C4)-alkyl;
Ar4 is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; said Ar4 being optionally substituted with up to three hydroxy, (C1-C4)alkoxy-(C1-C4)alkyl, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R36 and R37 are taken together on adjacent carbon atoms and are xe2x80x94Oxe2x80x94(CH2)txe2x80x94Oxe2x80x94;
t is 1, 2 or 3;
Y is (C2-C6)alkylene;
R44, R45 and R46 are each independently hydrogen or (C1-C4)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2, 3 or 4;
k is 0, 1, 2, 3 or 4;
Y1 is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R43 is (C3-C7)cycloalkyl, Ar5xe2x80x94(C0-C4)alkylenyl, NR47R48 or (C1-C6)alkyl optionally substituted with one to five fluoro; provided that when Y1 is a covalent bond or oxycarbonyl, then R43 is not NR47R48;
R47 and R48 are taken separately and are each independently selected from hydrogen, Ar5, (C1-C6)alkyl and Ar5xe2x80x94(C0-C4)alkylenyl; or
R47 and R48 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R47 and R48 are optionally substituted with one hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R47 and R48 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R47 and R48 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R47 and R48 are optionally substituted with up to three hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R47 and R48 are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
Ar5 is independently defined as set forth for Ar and Ar1 above;
Ar5 is optionally independently substituted as set forth for Ar and Ar1 above;
R42 and R42a are independently hydrogen, (C3-C7)cycloalkyl, Ar6xe2x80x94(C0-C3)alkylenyl, Ar6xe2x80x94(C2-C4)alkenyl, Ar6-carbonyl or (C1-C6)alkyl optionally substituted with up to five fluoro;
Ar6 is independently defined as set forth for Ar and Ar1 above;
Ar6 is optionally independently substituted as set forth for Ar and Ar1 above; and
R41 and R41a are each independently hydrogen or (C1-C4)alkyl.
A preferred group of compounds of formula I, designated Group A, are those compounds of formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R3 is 
xe2x80x83substituted by R18, R19 or R20;
G3, G4 and G5 are taken separately and are each hydrogen, r is 0 and R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl or phenyl optionally substituted by up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; R19 and R20 are each independently (C1-C4)alkyl;
G3, G4 and G5 are taken separately and are each hydrogen; r is 1; and R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl or phenyl optionally substituted by up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; R19 and R20 are each independently hydrogen or (C1-C4)alkyl; or
G3 and G4 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G5 are hydrogen; or
G4 and G5 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G3 are hydrogen;
R17 is SO2NR21R22, CONR21R22, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, Ar2-carbonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, Ar2-sulfonyl, Ar2-sufinyl and (C1-C6)alkyl;
R21 and R22 are taken separately and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl and Ar2xe2x80x94(C0-C4)alkylenyl; or
R21 and R22 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-isoquinolyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R21 and R22 is optionally substituted independently with one substituent selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl, morpholinyl, azepinyl in the definition of R21 and R22 are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R21 and R22 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of R21 and R22 is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl, (C1-C4)alkoxycarbonyl and (C1-C4)alkyl optionally substituted with up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R21 and R22 are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrimidyl, pyridyl and phenyl which are optionally substituted on said piperazine in the definition of R21 and R22 is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R21 and R22 is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro.
Another preferred group of compounds of formula I, designated Group B, are those compounds of formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R3 is 
R23 is CONR25R26, SO2R25R26, wherein R25 is hydrogen (C1-C4)alkyl or Ar3xe2x80x94(C0-C4)alkylenyl and R26 is Ar3xe2x80x94(C0-C4)alkylenyl; provided that when Ar3 is phenyl, naphthyl or biphenyl, then R23 cannot be CONR25R26 where R25 is hydrogen or Ar3 and R26 is Ar3;
R24 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl or phenyl optionally substituted by up to three (C1-C4)alkyl optionally substituted with up to five fluoro, (C1-C4)alkoxy optionally substituted with up to five fluoro, hydroxy, halo or hydroxy-(C1-C3)alkyl.
Another preferred group of compounds of formula I, designated Group C, are those compounds of formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R3 is 
R27 is hydrogen or (C1-C4)alkyl;
R28 and R29 are each independently hydrogen, hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro, (C1-C4)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, SO2NR30R31, CONR30R31 or NR30R31; said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R28 and R29 are optionally substituted by up to two hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R28 and R29 are optionally substituted by up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R30 and R31 are each independently hydrogen, (C1-C4)alkyl, (C3-C7)cycloalkyl or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R30 and R31 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyl in the definition of R30 and R31 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R30 and R31 are optionally substituted with up to three hydroxy, amino, or hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R30 and R31 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro.
Yet another preferred group of compounds of formula I, designated Group D, are those compounds of formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R3 is 
A is N optionally substituted with hydrogen or (C1-C4)alkyl and B is carbonyl; or
A is carbonyl and B is N optionally substituted with hydrogen or (C1-C4)alkyl;
R32 is hydrogen or (C1-C4)alkyl;
R33 is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl or benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R3 are optionally substituted with up to three phenyl, phenoxy, NR34R35, halo, hydroxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R34 and R35 are each independently hydrogen, (C1-C4 alkyl), phenyl or phenylsulfonyl;
said phenyl and phenylsulfonyl in the definition of R34 and R35 are optionally substituted with up to three halo, hydroxy, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro.
Still another preferred group of compounds of formula I, designated Group E, are those compounds of formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R3 is 
D is CO, CHOH or CH2;
E is O, NH or S;
R36 and R37 are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, pyrrolidino, piperidino, morpholino, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl, Ar4, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R38, R39 and R40 are each independently hydrogen or (C1-C4)-alkyl;
Ar4 is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; said Ar4 being optionally substituted with up to three hydroxy, (C1-C4)alkoxy-(C1-C4)alkyl, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R36 and R37 are taken together on adjacent carbon atoms and are xe2x80x94Oxe2x80x94(CH2)txe2x80x94Oxe2x80x94;
t is 1, 2 or 3.
Still another preferred group of compounds of formula I, designated Group F, are those compounds of formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R3 is 
Y is (C2-C6)alkylene;
R44, R45 and R46 are each independently hydrogen or (C1-C4)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2, 3 or 4;
k is 0 to 4;
Y1 is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R43 is (C3-C7)cycloalkyl, Ar5xe2x80x94(C0-C4)alkylenyl, NR47R48 or (C1-C6)alkyl optionally substituted with one to five fluoro; provided that when Y1 is a covalent bond or oxycarbonyl, then R43 is not NR47R48;
R47 and R48 are taken separately and are each independently selected from hydrogen, Ar5, (C1-C6)alkyl and Ar5xe2x80x94(C0-C4)alkylenyl; or
R47 and R48 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R47 and R48 are optionally substituted with one hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R47 and R48 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R47 and R48 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R47 and R48 are optionally substituted with up to three hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R47 and R48 are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro.
A preferred group of compounds within Group F, designated Group FA, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl;
R2 is hydrogen;
R3 is 
k is 0;
Y1 is a covalent bond; and
R43 is 4-pyrimidinyl substituted at the 2-position with 1-hydroxymethyl.
A preferred group of compounds within Group FA, designated Group FB, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, which is 1R-(4-{1xe2x80x2-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-[4,4xe2x80x2]bipiperidinyl-1-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds of formula I, designated Group G, are those compounds of formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R3 is 
R42 and R42a are independently hydrogen, (C3-C7)cycloalkyl, Ar6xe2x80x94(C0-C3)alkylenyl, Ar6xe2x80x94(C2-C4)alkenyl, Ar6-carbonyl or (C1-C6)alkyl optionally substituted with up to five fluoro; and
R41 and R41a are independently hydrogen or (C1-C4)alkyl.
Still another preferred group of compounds of formula I, designated Group H, are those compounds of formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R1 is C(OH)R4R5, where R4 and R5 are each independently hydrogen or methyl;
R2 is hydrogen;
R3 is 
xe2x80x83wherein said R3 is substituted by R6, R7 or R8;
G, G1 and G2 are taken separately and are each hydrogen and R6 is hydrogen or (C1-C4)alkyl; R7 and R8 are each independently hydrogen or (C1-C4)alkyl; or
G and G1 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G2 are hydrogen; or
G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G are hydrogen;
q is 0 or 1;
X is a covalent bond, oxycarbonyl, vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, thio(C1-C4)alkylenylcarbonyl or vinylenylsulfonyl; said vinylenylcarbonyl and said vinylenylsulfonyl in the definition of X are optionally substituted on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar; said oxy(C1-C4)alkylenylcarbonyl and said thio(C1-C4)alkylenylcarbonyl in the definition of X are optionally substituted with up to two (C1-C4)alkyl, benzyl or Ar;
R9 is (C3-C7)cycloalkyl, Ar1xe2x80x94(C0-C4)alkylenyl or (C1-C6)alkyl optionally substituted with up to five fluoro;
Ar1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl; and
said Ar1 is optionally substituted as set forth above.
A preferred group of compounds within Group H, designated Group HA, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
X is a covalent bond, oxycarbonyl or vinylenylcarbonyl optionally substituted on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar;
R9 is Ar1xe2x80x94(C0-C4)alkylenyl;
Ar1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, furanyl, thienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, furopyridyl, oxazolopyridyl, thiazolopyridyl, thienopyridyl, furopyrimidyl, thienopyrimidyl, oxazolopyrimidyl or thiazolopyrimidyl; and
said Ar1 is optionally substituted as set forth in claim 1.
A preferred group of compounds within Group HA, designated Group HB, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R2 is hydrogen;
R4 is hydrogen or methyl;
R5 is methyl;
G, G1 and G2 are hydrogen;
R6 and R7 are each independently hydrogen or methyl;
R8 is hydrogen.
A preferred group of compounds within Group HB, designated Group HC, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl; and
R3 is 
A preferred compound within Group HC is the compound wherein R9 is 2-furo[3,2-c]pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein R9 is 2-(4-chloro-furo[3,2-c]pyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein R9 is 2-(4-pyrrolidin-1-yl-furo[3,2-c]pyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein R9 is 2-(4-morpholin-4-yl-furo[3,2-c]pyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein R9 is 2-imidazo[1,2-a]pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within Group HC are furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone; (4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone; {4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-pyrrolidin-1-yl-furo[3,2-c]pyridin-2-yl)-methanone; {4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-morpholin-4-yl-furo[3,2-c]pyridin-2-yl)-methanone; and {4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-imidazo[1,2-a]pyridin-2-yl-methanone.
Another preferred group of compounds within Group HB, designated Group HD, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl; and
R3 is 
A preferred compound within Group HD is the compound wherein R9 is 2-furo[3,2-c]pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An especially preferred compound within Group HD is furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone.
Another preferred group of compounds within Group HB, designated Group HE, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl; and
R3 is 
A preferred compound within Group HE is the compound wherein R9 is 3-pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HE is the compound wherein R9 is 3-(2-methylpyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HE is the compound wherein R9 is 3-(5-chloropyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HE is the compound wherein R9 is 3-(6-methylpyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within Group HE are 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid pyridin-3-yl ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 2-methyl-pyridin-3-yl ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 5-chloro-pyridin-3-yl ester; and 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 6-methyl-pyridin-3-yl ester.
Another preferred group of compounds within Group HB, designated Group HF, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl; and
R3 is 
A preferred compound within the Group HF is the compound wherein R9 is 2-thienyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An especially preferred compound within Group HF is (E)-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-3-thiophen-2-yl-propenone.
Another preferred group of compounds within Group HB, designated Group HG, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl;
R3 is 
R9 is pyrimidyl or triazinyl; said pyrimidyl or triazinyl is optionally substituted with up to two hydroxy, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkylenyl, phenyl, piperazinyl optionally substituted with (C1-C4)alkyl, or imidazolyl optionally substituted with up to two (C1-C4)alkyl.
A preferred group of compounds within Group HG, designated Group HH, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R9 is pyrimid-2-yl optionally substituted with up to two (C1-C4)alkyl, hydroxy-(C1-C4)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl.
A preferred compound within the Group HH is the compound wherein R9 is 4,6-dimethylpyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HH is the compound wherein R9 is 4-methoxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HH is the compound wherein R9 is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred group of compounds within the Group HH are 1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; and 1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.
Another preferred group of compounds within the Group HG, designated HI, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R9 is pyrimid-4-yl optionally substituted with up to two (C1-C4)alkylpiperazin-1-yl or imidazolyl; and said imidazolyl is optionally substituted with up to two (C1-C4)alkyl.
A preferred compound within the Group HI is the compound wherein R9 is 2-(4-methylpiperazin-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HI is the compound wherein R9 is 2-(4-ethylpiperazin-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HI is the compound wherein R9 is 2-(4-methylimidazol-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug wherein.
Another preferred compound within the Group HI is the compound wherein R9 is 2-(2-methylimidazol-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug wherein.
Another preferred compound within the Group HI is the compound wherein R9 is 2-(2,4-dimethylimidazol-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HI is the compound wherein R9 is 2-(4-isopropylpiperazin-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within Group HI are 1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; and 1R-(4-{4-[2-(4-isopropyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within Group HG, designated Group HJ, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R9 is [1,3,5]-triazin-2-yl optionally substituted with up to two hydroxy, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkylpiperazin-1-yl or phenyl.
A preferred compound within the Group HJ is the compound wherein R9 is 4-methyl-6-(4-methylpiperazin-1-yl)-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound Within the Group HJ is the compound wherein R9 is 4-methoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4,6-dimethyoxy-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-ethoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-isopropoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-phenyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-hydroxymethyl-6-methoxy-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-isopropoxy-6-methoxy-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-isopropyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-ethyl-6-methoxy-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-cyclopropyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4,6-dimethyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-methyl-6-phenyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HJ are 1R-(4-{3R,5S-dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1-yl)-[1,3,5]triazin-2-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-ethoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropoxy-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[3R,5S-dimethyl-4-(4-methyl-6-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; and 1R-{4-[4-(4-ethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.
Another group of preferred compounds within the Group HB, designated Group HK, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl;
R3 is 
R9 is pyrimidyl or triazinyl, said pyrimidyl and triazinyl optionally substituted with up to two hydroxy, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1--C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, triazolyl, acetyl, morpholinyl, (C1-C4)alkylpiperazinyl, phenyl or imidazolyl optionally substituted with up to two (C1-C4)alkyl.
A preferred group of compounds within the Group HK, designated HL, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R9 is pyrimid-2-yl optionally substituted with up to two (C1-C4)alkyl, hydroxy-(C1-C4)alkyl or triazolyl.
A preferred compound within the Group HL is the compound wherein R9 is 4,6-dimethyl-pyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HL is the compound wherein R9 is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HL is the compound wherein R9 is 4-[1,2,4]-triazol-1-yl-pyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HL are 1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; and 1R-{4-[2R,6S-dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.
Another preferred group of compounds within the Group HK, designated Group HM, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R9 is pyrimid-4-yl optionally substituted with up to two (C1-C4)alkyl, hydroxy-(C1-C4)alkyl, acetyl, morpholinyl, (C1-C4)alkylpiperazinyl, triazolyl or imidazolyl optionally substituted with up to two (C1-C4)alkyl.
A preferred compound within the Group HM is the compound wherein R9 is 2,6-dimethyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-hydroxymethyl-6-methyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-acetyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-morpholin-4-yl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(4-methylpiperazin-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-[1,2,4]-triazol-1-yl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(1S-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(1R-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(4-ethylpiperazin-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(4-methylimidazol-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(2,4-dimethylimidazol-1-yl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the HB Group are 1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(1S-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; (4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone; 1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl)-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl)-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6R-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; and 1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
Another preferred compound within the Group HB is the compound wherein R1 is (R)-1-hydroxyethyl; R3 is 
R9 is 2-(1R-hydroxyethyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred group of compounds within the Group HK, designated Group HN, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein R9 is [1,3,5]-triazin-2-yl optionally substituted with up to two hydroxy, (C1-C4)alkyl, (C3-C7)cycloalkyl, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxy, morpholinyl or phenyl.
A preferred compound within the Group HN is the compound wherein R9 is 4-morpholin-4-yl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4-methoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4,6-dimethoxy-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4-phenyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4-cyclopropyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4,6-dimethyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4-hydroxymethyl-6-phenyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4-methoxy-6-methoxymethyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4-methoxymethyl-6-phenyl-[1,3,5]triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HN are 1R-{4-[2R,6S-dimethyl-4-(4-morpholin-4-yl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-methoxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; and 1R-{4-[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol.
Another preferred group of compounds within the Group HB, designated Group HO, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl;
R3 is 
R9 is pyrimidyl, quinoxalyl or oxazolopyridyl optionally substituted with up to two (C1-C4)alkyl, (C1-C4)alkoxy or hydroxy-(C1-C4)alkyl.
A preferred compound within the Group HO is the compound wherein R9 is 4-hydroxymethyl-6-methyl-pyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein R9 is 2-hydroxymethyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein R9 is 2-hydroxymethyl-6-methyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein R9 is 2-(oxazolo[5,4-b]pyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein R9 is 2-(oxazolo[4,5-b]pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein R9 is 2-quinoxalyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HO are 1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol; 1R-[4-(3S-methyl-4-oxazolo[4,5-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol; and 1R-[4-(3S-methyl-4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol.
Another preferred group of compounds within the Group HB, designated Group HP, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl;
R3 is 
R9 is pyrimidyl optionally substituted with up to two (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl.
A preferred compound within the Group HP is the compound wherein R9 is 2-(1R-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred compound within the Group HP is 1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R-methyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within the Group HB, designated HQ, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (R)-1-hydroxy-ethyl;
R3 is 
R9 is pyrimidyl optionally substituted with up to two (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl.
A preferred compound within the Group HQ is the compound wherein R9 is 2-(1R-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An especially preferred compound within the Group HQ is (4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within the Group HB, designated Group HR, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is (S)-1-hydroxy-ethyl;
R3 is 
R9 is pyrimidyl optionally substituted with up to two (C1-C4)alkyl, (C1-C4)alkoxy or hydroxy-(C1-C4)alkyl.
A preferred compound within the Group HR is the compound wherein R9 is 2-(1R-hydroxy-ethyl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An especially preferred compound within the Group HR is 1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
Yet another preferred group of compounds within the Group HB, designated Group HS, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R1 is acetyl;
R3 is 
R9 is pyrimidyl optionally substituted with up to two (C1-C4)alkyl, (C1-C4)alkoxy, acetyl or hydroxy-(C1-C4)alkyl.
A preferred compound within the Group HS is the compound wherein R9 is 2-acetyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred compound within the Group HS is the compound wherein R9 is 2-5 (1R-hydroxyethyl)-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Especially preferred compounds within the Group HS are 1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R*,6S*-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone or 1-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone.
A pharmaceutical composition, designated Composition A, comprising a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
A method of inhibiting sorbitol dehydrogenase in a mammal in need of such inhibition comprising administering to said mammal a sorbitol dehydrogenase inhibiting amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A method of treating diabetes in a mammal suffering from diabetes comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A method, designated Method A, of treating or preventing diabetic complications in a mammal comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A method of Method A wherein said mammal is suffering from diabetes.
A method of Method A wherein said diabetic complication is diabetic neuropathy.
A method of Method A wherein said diabetic complication is diabetic nephropathy.
A method of Method A wherein said diabetic complication is diabetic retinopathy.
A method of Method A wherein said diabetic complication is foot ulcers.
A method of Method A wherein said diabetic complication is a cardiovascular condition.
A pharmaceutical composition, designated Composition B, comprising a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said aldose reductase inhibitor or said prodrug.
A composition of Composition B additionally comprising a pharmaceutically acceptable carrier or diluent.
A method of treating diabetes in a mammal suffering from diabetes comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and an aldose reductase inhibitor, a prodrug of said aldose reductase inhibitor or a pharmaceutically acceptable salt of said aldose reductase inhibitor or said prodrug.
A method, designated Method B, of treating or preventing diabetic complications in a mammal comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable of said compound or said prodrug and an aldose reductase inhibitor, a prodrug of said aldose reductase inhibitor or a pharmaceutically acceptable salt of said aldose reductase inhibitor or said prodrug thereof.
A method of Method B wherein said mammal is suffering from diabetes.
A method of Method B wherein said diabetic complication is diabetic neuropathy.
A method of Method B wherein said diabetic complication is diabetic nephropathy.
A method of Method B wherein said diabetic complication is diabetic retinopathy.
A method of Method B wherein said diabetic complication is foot ulcers.
A method of Method B wherein said diabetic complication is a cardiovascular condition.
A pharmaceutical composition, designated Composition C, comprising a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or a pharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrug thereof.
A method, designated Method C, of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal an effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or a pharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrug.
A method of Method C wherein said ischemia is perioperative myocardial ischemia.
A method of treating or preventing diabetic complications in a mammal, designated Method D, comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or a pharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrug.
A method of Method D wherein said mammal is suffering from diabetes.
A method of Method D wherein said diabetic complication is diabetic neuropathy.
A method of Method D wherein said diabetic complication is diabetic nephropathy.
A method of Method D wherein said diabetic complication is diabetic retinopathy.
A method of Method D wherein said diabetic complication is foot ulcers.
A method of Method D wherein said diabetic complication is a cardiovascular condition.
A method of treating diabetes in a mammal suffering from diabetes comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or a pharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrug.
A kit comprising:
a. a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug in a first unit dosage form;
b. an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said aldose reductase inhibitor in a second unit dosage form; and
c. a container.
A kit comprising:
a. a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug in a first unit dosage form;
b. a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said NHE-1 inhibitor in a second unit dosage form; and
c. a container.
A method, designated Method E, of inhibiting sorbitol dehydrogenase in a mammal in need thereof comprising administering to said mammal Composition A.
A method of Method E wherein said ischemia is perioperative myocardial ischemia.
A method of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal Composition C.
A method, designated Method F, of treating or preventing diabetic complications in a mammal comprising administering to said mammal Composition A.
A method of Method F wherein said mammal is suffering from diabetes.
A method, designated Method G, of treating or preventing diabetic complications in a mammal comprising administering to said mammal Composition B.
A method of Method G wherein said mammal is suffering from diabetes.
A method, designated Method H, of treating or preventing diabetic complications in a mammal comprising administering to said mammal Composition C.
A method of Method H wherein said mammal is suffering from diabetes.
A compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
R1 is C(OH)R4R5, where R4 and R5 are each independently hydrogen or methyl;
R2 is hydrogen;
R3 is 
xe2x80x83wherein said piperazinyl R3 is substituted by R6, R7 or R8;
G, G1 and G2 are taken separately and are each hydrogen and R6 is hydrogen or (C1-C4)alkyl; R7 and R8 are each independently hydrogen or (C1-C4)alkyl; or
G and G1 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G2 are hydrogen; or
G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G are hydrogen;
q is 0 or 1;
X is a covalent bond, oxycarbonyl,vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, thio(C1-C4)alkylenylcarbonyl or vinylenylsulfonyl; said vinylenylcarbonyl and said vinylenylsulfonyl in the definition of X are optionally substituted on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar; said oxy(C1-C4)alkylenylcarbonyl and said thio(C1-C4)alkylenylcarbonyl in the definition of X are optionally substituted with up to two (C1-C4)alkyl, benzyl or Ar;
R9 is (C3-C7)cycloalkyl, Ar1xe2x80x94(C0-C4)alkylenyl or (C1-C6)alkyl optionally substituted with up to five fluoro;
Ar1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl; and
said Ar1 is optionally substituted as set forth above;
k is 0, 1, 2, 3 or 4;
Y1 is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R43 is (C3-C7)cycloalkyl, Ar5xe2x80x94(C0-C4)alkylenyl, NR47R48 or (C1-C6)alkyl optionally substituted with one to five fluoro; provided that when Y1 is a covalent bond or oxycarbonyl, then R43 is not NR47R48;
R47 and R48 are taken separately and are each independently selected from hydrogen, Ar5, (C1-C6)alkyl and Ar5xe2x80x94(C0-C4)alkylenyl; or
R47 and R48 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R47 and R48 are optionally substituted with one hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R47 and R48 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R47 and R48 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R47 and R48 are optionally substituted with up to three hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R47 and R48 are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
Ar5 is independently defined as set forth for Ar and Ar1 above;
Ar5 is optionally independently substituted as set forth for Ar and Ar1 above.
A compound selected from 1R-(4-{1xe2x80x2-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-[4,4]bipiperidinyl-1-yl}-pyrimidin-2-yl)-ethanol; furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone; (4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone; {4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-pyrrolidin-1-yl-furo[3,2-c]pyridin-2-yl)-methanone; {4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-morpholin-4-yl-furo[3,2-c]pyridin-2-yl)-methanone; {4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-imidazo[1,2-a]pyridin-2-yl-methanone; furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid pyridin-3-yl ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 2-methyl-pyridin-3-yl ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 5-chloro-pyridin-3-yl ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid 6-methyl-pyridin-3-yl ester; (E)-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-3-thiophen-2-yl-propenone; 1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl)-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-isopropyl-piperazin-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1-yl)-[1,3,5]triazin-2-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-ethoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropoxy-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-ethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(1S-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone; 1RS-(4-{4-[2-(1RS-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; (4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone; 1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6R-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-morpholin-4-yl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol; 1R-[4-(3S-methyl-4-oxazolo[4,5-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol; 1R-[4-(3S-methyl-4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol; (4-{4-[2-(1R-hydroxyethyl)-pyrimidin-4-yl]-2R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[3R,5S-dimethyl-4-(4-methyl-6-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl-ethanol; 1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R*,6S*-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone; 1-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone; 1R-{4-[4-(4-methoxymethyl-6-phenyl-[1,3,5]-triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; and 1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
A compound of the formula IA
wherein:
R1 is Cxe2x80x94(OR80)R4R5, where R80 is independently (C1-C4)alkyl, benzyl, (C1-C6)alkylcarbonyl or phenylcarbonyl, where said benzyl and said phenyl are optionally substituted with up to three (C1-C4)alkyl, (C1-C4)alkoxy, halo or nitro;
R4 and R5 are each independently hydrogen, methyl, ethyl or hydroxy-(C1-C3)alkyl;
R2 is hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy;
R3 is a radical of the formula 
xe2x80x83wherein said radical of formula R3a is substituted by R6, R7 and R8;
said radical of formula R3b is substituted by R18, R19 and R20;
G, G1 and G2 are taken separately and are each hydrogen and R6 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1--C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; R7 and R8 are each independently hydrogen or (C1-C4)alkyl; or
G and G1 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G2 are hydrogen; or
G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G are hydrogen;
q is 0 or 1;
X is a covalent bond, xe2x80x94(Cxe2x95x90NR10)xe2x80x94, oxycarbonyl, vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl, thio(C1-C4)alkylenylcarbonyl, vinylenylsulfonyl, sulfinyl-(C1-C4)alkylenylcarbonyl, sulfonyl-(C1-C4)alkylenylcarbonyl or carbonyl(C0-C4)alkylenylcarbonyl; wherein said oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl and thio(C1-C4)alkylenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C1-C4)alkyl, benzyl or Ar; said vinylenylsulfonyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar; and said carbonyl(C0-C4)alkylenylcarbonyl in the definition of X is optionally substituted independently with up to three (C1-C4)alkyl, benzyl or Ar;
R10 is hydrogen or (C1-C4)alkyl;
R9 is (C3-C7)cycloalkyl, Ar1xe2x80x94(C0-C3)alkylenyl or (C1-C6)alkyl optionally substituted with up to five fluoro; provided that when q=0 and X is a covalent bond, oxycarbonyl or (C1-C4)alkylenylcarbonyl, then R9 is not (C1-C6)alkyl;
Ar and Ar1 are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five- to seven-membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocyclic ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
Ar and Ar1 are optionally independently substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to a total of four substituents independently selected from R11, R12, R13 and R14; wherein R11, R12, R13 and R14 are each taken separately and are each independently halo, formyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, C(OH)R15R16, naphthyl, phenyl, imidazolyl, pyridyl, triazolyl, morpholinyl, (C0-C4)alkylsulfamoyl, Nxe2x80x94(C0-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, N-phenylcarbamoyl, Nxe2x80x94(C1-C4)alkyl-N-phenylcarbamoyl, N,N-diphenyl carbamoyl, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, 8-(C1-C4)alkyl-3,8-diaza[3.2.1]bicyclooctyl, 3,5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfanyl, (C3-C7)cycloalkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl, thienyl, benzothiazolyl, pyrrolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the definition of R11, R12, R13 and R14 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of R11, R12, R13 and R14 are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from (C1-C4)alkyl; said pyrrolidinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from hydroxy, hydroxy-(C1-C3)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to three substituents independently selected from (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, (C0-C4)alkylsulfamoyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said triazolyl in the definition of R11, R 12, R13 and R14 is optionally substituted with hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said tetrazolyl in the definition of R11, R12, R13 and R14 is optionally substituted with hydroxy-(C2-C3)alkyl or (C1-C4)alkyl optionally substituted with up to five fluoro; and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R11, R12, R13 and R14 are optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R11 and R12 are taken together on adjacent carbon atoms and are xe2x80x94CH2OC(CH3)2OCH2xe2x80x94 or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94, and R13 and R14 are taken separately and are each independently hydrogen or (C1-C4)alkyl;
p is 1, 2or 3;
R15 and R16 are taken separately and are each independently hydrogen, (C1-C4)alkyl optionally substituted with up to five fluoro; or R15 and R16 are taken separately and R15 is hydrogen and R16 is (C3-C6)cycloalkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or benzoxazolyl; or R15 and R16 are taken together and are (C3-C6)alkylene;
G3, G4 and G5 are taken separately and are each hydrogen; r is 0; R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; and R19 and R20 are each independently (C1-C4)alkyl; or
G3, G4 and G5 are taken separately and are each hydrogen; r is 1; R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; and R19 and R20 are each independently hydrogen or (C1-C4)alkyl; or
G3 and G4 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G5 are hydrogen; or
G4 and G5 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G3 are hydrogen;
R17 is SO2NR21R22, CONR21R22, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, Ar2-carbonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, Ar2-sulfonyl, Ar2-sufinyl and (C1-C6)alkyl;
R21 and R22 are taken separately and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl and Ar2xe2x80x94(C0-C4)alkylenyl; or
R21 and R22 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 6,7-dihydro5H-dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-isoquinolyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R21 and R22 is optionally substituted independently with one substituent selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl, azepinyl in the definition of R21 and R22 are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R21 and R22 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of R21 and R22 is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl, (C1-C4)alkoxycarbonyl and (C1-C4)alkyl optionally substituted with up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R21 and R22 are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R21 and R22 is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrimidyl, pyridyl and phenyl which are optionally substituted on said piperazine in the definition of R21 and R22 is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
Ar2 is independently defined as set forth for Ar and Ar1 above; said Ar2 is optionally independently substituted as set forth for Ar and Ar1 above;
R23 is CONR25R26 or SO2R25R26, wherein R25 is hydrogen (C1-C4)alkyl or Ar3xe2x80x94(C0-C4)alkylenyl and R26 is Ar3xe2x80x94(C0-C4)alkylenyl; provided that when Ar3 is phenyl, naphthyl or biphenyl, then R23 cannot be CONR25R26 where R25 is hydrogen or Ar3 and R26 is Ar3;
R24 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro;
Ar3 is independently defined as set forth for Ar and Ar1 above; said Ar3 is optionally independently substituted as set forth for Ar and Ar1 above;
R27 is hydrogen or (C1-C4)alkyl;
R28 and R29 are each independently hydrogen, hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro, (C1-C4)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, SO2NR30R31, CONR30R31 or NR30R31; said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R28 and R29 are optionally substituted by up to two hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R28 and R29 are optionally substituted by up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R30 and R31 are each independently hydrogen, (C1-C4)alkyl, (C3-C7)cycloalkyl or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R30 and R31 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyl in the definition of R30 and R31 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R30 and R31 are optionally substituted with up to three hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R30 and R31 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C1-C4)alkyl and B is carbonyl; or
A is carbonyl and B is N optionally substituted with hydrogen or (C1-C4)alkyl;
R32 is hydrogen or (C1-C4)alkyl;
R33 is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl or benzothienyl; said phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R33 are optionally substituted with up to three phenyl, phenoxy, NR34R35, halo, hydroxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R34 and R35 are each independently hydrogen; (C1-C4 alkyl), phenyl or phenylsulfonyl; said phenyl and phenylsulfonyl in the definition of R34 and R35 are optionally substituted with up to three halo, hydroxy, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
D is CO, CHOH or CH2;
E is O, NH or S;
R36 and R37 are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, pyrrolidino, piperidino, morpholino, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl, Ar4, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R38, R39 and R40 are each independently hydrogen or (C1-C4)-alkyl;
Ar4 is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyrdazinyl; said Ar4 being optionally substituted with up to three hydroxy, (C1-C4)alkoxy-(C1-C4)alkyl, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R36 and R37 are taken together on adjacent carbon atoms and are xe2x80x94Oxe2x80x94(CH2)txe2x80x94Oxe2x80x94;
t is 1, 2 or 3;
Y is (C2-C6)alkylene;
R44, R45 and R46 are each independently hydrogen or (C1-C4)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2, 3 or 4;
k is 0, 1, 2, 3 or 4;
Y1 is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R43 is (C3-C7)cycloalkyl, Ar5xe2x80x94(C0-C4)alkylenyl, NR47R48 or (C1-C6)alkyl optionally substituted with one to five fluoro; provided that when Y1 is a covalent bond or oxycarbonyl, then R43 is not NR47R48;
R47 and R48 are taken separately and are each independently selected from hydrogen, Ar5, (C1-C6)alkyl and Ar5xe2x80x94(C0-C4)alkylenyl; or
R47 and R48 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R47 and R48 are optionally substituted with one hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R47 and R48 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R47 and R48 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R47 and R48 are optionally substituted with up to three hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R47 and R48 are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
Ar5 is independently defined as set forth for Ar and Ar1 above;
Ar5 is optionally independently substituted as set forth for Ar and Ar1 above;
R42 and R42a are independently hydrogen, (C3-C7)cycloalkyl, Ar6xe2x80x94(C0-C3)alkylenyl, Ar6xe2x80x94(C2-C4)alkenyl, Ar6-carbonyl or (C1-C6)alkyl optionally substituted with up to five fluoro;
Ar6 is independently defined as set forth for Ar and Ar1 above;
Ar6 is optionally independently substituted as set forth for Ar and Ar1 above; and
R41 and R41a are each independently hydrogen or (C1-C4)alkyl.
A compound of formula 1A selected from 1R-(4-{4-[2-(1R-butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate; 1R-(4-{4-[2-(1S-butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate; 1S-(4-{4-[2-(1R-butyryloxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate; (E)-1R-{4-[4-(2-methyl-32-phenyl-acryloyl)-piperazin-1-yl]-pyrimidin-2-yl}-ethyl acetate; (R)-1-[4-(4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl acetate; 1R-(4-{4-[2-(1RS-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate; 1RS-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate; 1R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate; 1R-{4-[3R,5S-dimethyl-4-(4-methyl-6-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; 1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; 1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; 1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; 1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; 1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl)-R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl)ethyl butyrate; and 1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate.
This invention is also directed to a mutual prodrug of the formula IB, 
wherein:
R1 is Cxe2x80x94(OR81)R4R5, where R81is independently an acyl radical of a carboxylic acid aldose reductase inhibitor;
R4 and R5 are each independently hydrogen, methyl, ethyl or hydroxy-(C1-C3)alkyl;
R2 is hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy;
R3 is a radical of the formula 
xe2x80x83wherein said radical of formula R3a is substituted by R6, R7 and R8; said radical of formula R3b is substituted by R18, R19 and R20;
G, G1 and G2 are taken separately and are each hydrogen and R6 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; R7 and R3 are each independently hydrogen or (C1-C4)alkyl; or
G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G2 are hydrogen; or
G1 and G2 are taken together and are (C1-C3)alkylene and R6, R7, R8 and G are hydrogen;
q is 0 or 1;
X is a covalent bond, xe2x80x94(Cxe2x95x90NR10)xe2x80x94, oxycarbonyl, vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl, thio(C1-C4)alkylenylcarbonyl, vinylenylsulfonyl, sulfinyl-(C1-C4)alkylenylcarbonyl, sulfonyl-(C1-C4)alkylenylcarbonyl or carbonyl(C1-C4)alkylenylcarbonyl; wherein said oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl and thio(C1-C4)alkylenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C1-C4)alkyl, benzyl or Ar; said vinylenylsulfonyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinylenyl carbons with (C1-C4)alkyl, benzyl or Ar; and said carbonyl(C0-C4)alkylenylcarbonyl in the definition of X is optionally substituted indepedently with up to three (C1-C4)alkyl, benzyl or Ar;
R10 is hydrogen or (C1-C4)alkyl;
R9 is (C3-C7)cycloalkyl, Ar1xe2x80x94(C0-C3)alkylenyl or (C1-C6)alkyl optionally substituted with up to five fluoro; provided that when q=0 and X is a covalent bond, oxycarbonyl or (C1-C4)alkylenylcarbonyl, then R9 is not (C1-C6)alkyl;
Ar and Ar1 are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five- to seven-membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocyclic ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
Ar and Ar1 are optionally independently substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to a total of four substituents independently selected from R11, R12, R13 and R14; wherein R11, R12, R13 and R14 are each taken separately and are each independently halo, formyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, C(OH)R15R16, naphthyl, phenyl, imidazolyl, pyridyl, triazolyl, morpholinyl, (C0-C4)alkylsulfamoyl, Nxe2x80x94(C0-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, N-phenylcarbamoyl, Nxe2x80x94(C1-C4)alkyl-N-phenylcarbamoyl, N,N-diphenyl carbamoyl, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, 8-(C1-C4)alkyl-3,8-diaza[3.2.1]bicyclooctyl, 3,5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfonyl, (C3-C7)cycloalkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl, thienyl, benzothiazolyl, pyrrolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the definition of R11, R12, R13 and R14 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of R11, R12, R13 and R14 are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from (C1-C4)alkyl; said pyrrolidinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to two substituents independently selected from hydroxy, hydroxy-(C1-C3)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of R11, R12, R13 and R14 is optionally substituted with up to three substituents independently selected from (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, (C0-C4)alkylsulfamoyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said triazolyl in the definition of R11, R12, R13 and R14 is optionally substituted with hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said tetrazolyl in the definition of R11, R12, R13 and R14 is optionally substituted with hydroxy-(C2-C3)alkyl or (C1-C4)alkyl optionally substituted with up to five fluoro; and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R11, R12, R13 and R14 are optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R11 and R12 are taken together on adjacent carbon atoms and are xe2x80x94CH2OC(CH3)2OCH2xe2x80x94 or xe2x80x94O-(CH2)pxe2x80x94Oxe2x80x94, and R13 and R14 are taken separately and are each independently hydrogen or (C1-C4)alkyl;
p is 1, 2 or 3;
R15 and R16 are taken separately and are each independently hydrogen, (C1-C4)alkyl optionally substituted with up to five fluoro; or R15 and R16 are taken separately and R15 is hydrogen and R16 is (C3-C6)cycloalkyl, hydroxy-(C1-C3)alkyl, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or benzoxazolyl; or R15 and R16 are taken together and are (C3-C6)alkylene;
G3, G4 and G5 are taken separately and are each hydrogen; r is 0; R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; and R19 and R20 are each independently (C1-C4)alkyl; or
G3, G4 and G5 are taken separately and are each hydrogen; r is 1; R18 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro; and R19 and R20 are each independently hydrogen or (C1-C4)alkyl; or
G3 and G4 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G5 are hydrogen; or
G4 and G5 are taken together and are (C1-C3)alkylene; r is 0 or 1; and R18, R19, R20 and G3 are hydrogen;
R17 is SO2NR21R22, CONR21R22, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, Ar2-carbonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, Ar2-sulfonyl, Ar2-sufinyl and (C1-C6)alkyl;
R21 and R22 are taken separately and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl and Ar2xe2x80x94(C0-C4)alkylenyl; or
R21 and R22 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-isoquinolyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R21 and R22 is optionally substituted independently with one substituent selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl, azepinyl in the definition of R21 and R22 are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R21 and R22 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of R21 and R22 is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl, (C1-C4)alkoxycarbonyl and (C1-C4)alkyl optionally substituted with up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of R21 and R22 are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R21 and R22 is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrimidyl, pyridyl and phenyl which are optionally substituted on said piperazine in the definition of R21 and R22 is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
Ar2 is independently defined as set forth for Ar and Ar1 above;
said Ar2 is optionally independently substituted as set forth for Ar and Ar1 above;
R23 is CONR25R26 or SO2R25R26, wherein R25 is hydrogen (C1-C4)alkyl or Ar3xe2x80x94(C0-C4)alkylenyl and R26 is Ar3xe2x80x94(C0-C4)alkylenyl; provided that when Ar3 is phenyl, naphthyl or biphenyl, then R23 cannot be CONR25R26 where R25 is hydrogen or Ar3 and R28 is Ar3;
R24 is hydrogen, (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl or (C1-C4)alkoxy, wherein said (C1-C4)alkyl in the definition of R6 and said (C1-C4)alkoxy in the definition of R6 are optionally and independently substituted with up to five fluoro;
Ar3 is independently defined as set forth for Ar and Ar1 above;
said Ar3 is optionally independently substituted as set forth for Ar and Ar1 above;
R27 is hydrogen or (C1-C4)alkyl;
R28 and R29 are each independently hydrogen, hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro, (C1-C4)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, SO2NR30R31, CONR30R31 or NR30R31; said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R28 and R29 are optionally substituted by up to two hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R28 and R29 are optionally substituted by up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R30 and R31 are each independently hydrogen, (C1-C4)alkyl, (C3-C7)cycloalkyl or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R30 and R31 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyl in the definition of R30 and R31 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R30 and R31 are optionally substituted with up to three hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R30 and R31 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C1-C4)alkyl and B is carbonyl; or
A is carbonyl and B is N optionally substituted with hydrogen or (C1-C4)alkyl;
R32 is hydrogen or (C1-C4)alkyl;
R33 is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl or benzothienyl; said phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R33 are optionally substituted with up to three phenyl, phenoxy, NR34R35, halo, hydroxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R34 and R35 are each independently hydrogen, (C1-C4 alkyl), phenyl or phenylsulfonyl; said phenyl and phenylsulfonyl in the definition of R34 and R35 are optionally substituted with up to three halo, hydroxy, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
D is CO, CHOH or CH2;
E is O, NH or S;
R36 and R37 are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, pyrrolidino, piperidino, morpholino, (C1-C4)alkoxy-(C1-C4)alkyl, hydroxy-(C1-C4)alkyl, Ar4, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
R38, R39 and R40 are each independently hydrogen or (C1-C4)-alkyl;
Ar4 is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; said Ar4 being optionally substituted with up to three hydroxy, (C1-C4)alkoxy-(C1-C4)alkyl, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; or
R36 and R37 are taken together on adjacent carbon atoms and are xe2x80x94Oxe2x80x94(CH2)txe2x80x94Oxe2x80x94;
t is 1, 2 or 3;
Y is (C2-C6)alkylene;
R44, R45 and R48 are each independently hydrogen or (C1-C4)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2, 3 or 4;
k is 0, 1, 2, 3 or 4;
Y1 is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R43 is (C3-C7)cycloalkyl, Ar5xe2x80x94(C0-C4)alkylenyl, NR47R48 or (C1-C6)alkyl optionally substituted with one to five fluoro; provided that when Y1 is a covalent bond or oxycarbonyl, then R43 is not NR47R48;
R47 and R48 are taken separately and are each independently selected from hydrogen, Ar5, (C1-C6)alkyl and Ar5xe2x80x94(C0-C4)alkylenyl; or
R47 and R48 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R47 and R48 are optionally substituted with one hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R47 and R48 are optionally substituted with up to two hydroxy, amino, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R47 and R48 is optionally substituted with up to two substituents independently selected from hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R47 and R48 are optionally substituted with up to three hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R47 and R48 are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro;
Ar5 is independently defined as set forth for Ar and Ar1 above;
Ar5 is optionally independently substituted as set forth for Ar and Ar1 above;
R42 and R42a are independently hydrogen, (C3-C7)cycloalkyl, Ar6xe2x80x94(C0-C3)alkylenyl, Ar6xe2x80x94(C2-C4)alkenyl, Ar6-carbonyl or (C1-C6)alkyl optionally substituted with up to five fluoro;
Ar6 is independently defined as set forth for Ar and Ar1 above;
Ar6 is optionally independently substituted as set forth for Ar and Ar1 above; and
R41 and R41a are each independently hydrogen or (C1-C4)alkyl.
A preferred group of compounds within the compound of formula IB are those compounds wherein R81is the acyl radical of ponalrestat, tolrestat, zenarastat, zopolrestat, epalrestat, ZD5522 or sorbinil.
Especially preferred mutual prodrugs of this invention are selected from (E)-[4-oxo-3-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid 1R-[4-(4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl ester and (E)-[4-Oxo-3-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid 1R-(4-[4-(3-thiophen-2-yl-acryloyl)-piperazin-1-yl]-pyrimidin-2-yl}-ethyl ester.
This invetion is also directed to intermediate compounds of the formula Z 
This invention is still further directed to intermediate compounds, designated Group AA, of the formula ZZ, 
wherein R100 is (C1-C8)alkyl, benzyl or phenyl wherein said benzyl and phenyl are optionally substituted with up to three halo or (C1-C4)alkyl.
A preferred group of compounds within Group AA, designated Group AB, are those compounds wherein R100 is (C1-C4)alkyl.
More preferred compounds within the Group AB are those compounds wherein R100 is n-butyl or ethyl.
This invention is still further directed to a compound of the formula ZZZ, 
wherein:
R100 is (C1-C8)alkyl, benzyl or phenyl wherein said benzyl and phenyl are optionally substituted with up to three halo or (C1-C4)alkyl; and
R101 is hydrogen or a suitable amine protecting group.
A preferred group of compounds of formula ZZZ, designated Group AC, are those compounds wherein R100 is (C1-C4)alkyl and R101 is benzyl or tert-butyloxycarbonyl.
A preferred group of compounds within the Group AC are those compounds wherein R100 is n-butyl or ethyl and R101 is benzyl.
Another preferred group of compounds within the Group AC are those compounds wherein R100 is n-butyl or ethyl and R101 is tert-butyloxycarbonyl.
This invention is also directed to a process for preparing a compound of the formula Z, 
comprising:
a) reacting R-(+)-2-hydroxy-propionamide with triethyloxonium tetrafluoroborate in a reaction inert solvent for 10 minutes to 24 hours at 0xc2x0 C. to ambient temperature to form the corresponding imidate;
b) reacting said corresponding imidate with anhydrous ammonia in a reaction inert solvent for 2 hours to 24 hours at 0xc2x0 C. to ambient temperature to form R-(+)-2-hydroxy-propionamidine hydrochloride; and
c) reacting said R-(+)-2-hydroxy-propionamidine hydrochloride with ethyl 3-hydroxy-acrylate sodium salt and a suitable base in a reaction inert solvent to form said compound of formula Z.
This invention is also directed to a pharmaceutical composition, designated Composition AA, comprising a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound, and a glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharmaceutically acceptable salt of said GPI or said prodrug.
This invention is also directed to a kit comprising:
a. a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound in a first unit dosage form;
b. a glycogen phosphorylase inhibitor (GPI), a prod rug thereof or a pharmaceutically acceptable salt of said prodrug or said GPI in a second unit dosage form; and
c. a container.
This invention is also directed to a method of treating or preventing diabetic complications in a mammal comprising administering to said mammal a pharmaceutical composition of Composition AA.
This invention is also directed to a method of treating hyperglycemia in a mammal comprising administering to said mammal a pharmaceutical composition of Composition AA.
This invention is also directed to a method of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal a pharmaceutical composition of Composition AA.
This invention is also directed to a method of treating diabetes in a mammal comprising adminstering to said mammal a pharmaceutical composition of Composition AA.
This invention is also directed to a method of treating diabetic complications in a mammal comprising adminstering to said mammal a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharmaceutically acceptable salt of said GPI or said prodrug.
This invention is also directed to a method of treating hyperglycemia in a mammal comprising administering to said mammal a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prod rug and a glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharmaceutically acceptable salt of said GPI or said prodrug.
This invention is also directed to a method of treating ischemia in a mammal comprising adminstering to said mammal a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharmaceutically acceptable salt of said GPI or said prodrug.
This invention is also directed to a method of treating diabetes in a mammal comprising administering to said mammal a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharmaceutically acceptable salt of said GPI or said prodrug.
The subject invention also includes isotopically-labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which racioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The term xe2x80x9creductionxe2x80x9d is intended to include partial prevention or prevention which, although greater than that which would result from taking no compound or from taking a placebo, is less than 100% in addition to substantially total prevention.
The term xe2x80x9cdamage resulting from ischemiaxe2x80x9d as employed herein refers to conditions directly associated with reduced blood flow to tissue, for example due to a clot or obstruction of blood vessels which supply blood to the subject tissue and which result, inter alia, in lowered oxygen transport to such tissue, impaired tissue performance, tissue dysfunction and/or necrosis. Alternatively, where blood flow or organ perfusion may be quantitatively adequate, the oxygen carrying capacity of the blood or organ perfusion medium may be reduced, e.g., in hypoxic environment, such that oxygen supply to the tissue is lowered, and impaired tissue performance, tissue dysfunction, and/or tissue necrosis ensues.
The term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The expression xe2x80x9cprodrugxe2x80x9d refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
This invention is further directed to compounds which are mutual prodrugs of aldose reductase inhibitors and sorbitol dehydrogenase inhibitors. By mutual prodrug is meant a compound which contains two active components, in this case, an aldose reductase inhibitor and a sorbitol dehydrogenase inhibitor, which, following administration, is cleaved, releasing each individual active component. Such mutual prodrugs of an aldose reductase inhibitor and a sorbitol dehydrogenase inhibitor are formed under standard esterification conditions well known to those skilled in the art.
By alkylene is meant saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene.
By halo is meant chloro, bromo, iodo, or fluoro.
By alkyl is meant straight chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxygen. Exemplary of such alkoxy groups (assuming the designated length encompasses.the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.
It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term xe2x80x9cpyridylxe2x80x9d means 2-, 3-, or 4-pyridyl, the term xe2x80x9cthienylxe2x80x9d means 2-, or 3-thienyl, and so forth.
The expression xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate. Where more than one basic moiety exists the expression includes multiple salts (e.g., di-salt). The expression also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,Nxe2x80x2-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
As used herein, the expressions xe2x80x9creaction inert solventxe2x80x9d and xe2x80x9cinert solventxe2x80x9d refers to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The chemist of ordinary skill will recognize that certain compounds of formula I of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Compounds of formula I may be chiral. In such cases, the isomer wherein R1 has the R configuration is preferred. Hydrates of the compounds of formula I of this invention are also included.
The chemist of ordinary skill in the art will also recognize that certain compounds of formula I of this invention can exist in tautomeric form, i.e., that an equilibrium exists between two isomers which are in rapid equilibrium with each other. A common example of tautomerism is keto-enol tautomerism, i.e., 
Examples of compounds which can exist as tautomers include hydroxypyridines, hydroxypyrmidines and hydroxyquinolines. Other examples will be recognized by those skilled in the art. All such tautomers and mixtures thereof are included in this invention.
DMF means N,N-dimethylformamide. DMSO means dimethyl sulfoxide. THF means tetrahydrofuran.
Whenever the structure of a cyclic radical is shown with a bond drawn from outside the ring to inside the ring, it will be understood by those of ordinary skill in the art to mean that the bond may be attached to any atom on the ring with an available site for bonding. If the cyclic radical is a bicyclic or tricyclic radical, then the bond may be attached to any atom on any of the rings with an available site for bonding. For example, 
represents any or all of the following radicals: 
Other features and advantages will be apparent from the specification and claims which describe the invention.
In general the compounds of formula I of this invention can be made by processes which include processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of formula I of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes are described in the experimental section. 
Compounds of formula 1-3 (i.e., formula 1) are prepared as set forth in Scheme 1, particularly as described below.
Compounds of formula 1-3 are prepared by the displacement reaction of a pyrimidine of the formula 1-1 where R1 and R2 are defined herein. Lv is a leaving group preferably selected from fluoro, chloro, bromo, iodo, thiomethyl, methylsulfone, or OSO2J wherein J is (C1-C6)-lower alkyl, trifluoromethyl, pentafluoroethyl, phenyl optionally substituted with up to three (C1-C4)alkyl, nitro or halo. The leaving group Lv is displaced by an amine of the formula 1-2 where R3 is defined above. The reaction is conducted in the presence of a non-aqueous base, preferably an organic amine or an inorganic base. Preferred organic amines include triethylamine, pyridine, dimethylaminopyridine and N,Nxe2x80x2-diisopropylethylamine (Hunig""s base). Preferred inorganic bases include alkaline metal carbonates and bicarbonates such as sodium or potassium carbonate and sodium or potassium bicarbonate. An especially preferred inorganic base is potassium carbonate. An especially preferred organic amine is triethylamine. Alternatively, an excess of the reacting amine 1-2 can be used as the base for this reaction. The reaction can be conducted in the absence of solvent or in a reaction inert solvent. Where used herein, xe2x80x9creaction inert solventxe2x80x9d refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. Preferred reaction inert solvents include aqueous media, pyridine, (C1-C4)alcohol, (C2-C6)glycol, halocarbon, aliphatic/aromatic hydrocarbon, ethereal solvent, polar aprotic solvent, ketonic solvent, or combinations thereof. The reaction time ranges from 15 minutes to 3 days and the reaction temperature ranges from 0xc2x0 C. to 180xc2x0 C. Conveniently, the reaction may be conducted at the reflux temperature of the solvent being used. The reaction is preferably conducted at ambient pressure. The term ambient pressure, where used herein, refers to the pressure of the room in which the reaction is being conducted. The term ambient temperature, where used herein, refers to the temperature of the room in which the reaction is being conducted.
When R1 contains a hydroxy group, the hydroxyl group may or may not be protected. When the hydroxyl group is protected, the protecting group may be any suitable hydroxyl protecting group. The conditions used to remove such optional hydroxyl protecting groups contained in R1 in compounds of formula 1-3 are as follows. When the protecting group is an ester, removal of such ester protecting groups is conducted under basic conditions using inorganic hydroxides or carbonates, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide or potassium carbonate. The reaction is carried out in a reaction inert solvent, preferably an alcoholic solvent. Especially preferred is methanol or methanol in combination with co-solvents such as water, tetrahydrofuran, or dioxane. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from 0xc2x0 C. to 100xc2x0 C. or to the reflux temperature of the solvent(s) of use. Alternatively, ester cleavage may be accomplished under acidic conditions. It is preferred to utilize aqueous hydrochloric acid, generally 2 N to concentrated, with or without a co-solvent. When a co-solvent is used, dioxane or methanol are preferred. The reaction time ranges from 4 hours to 3 days and the reaction temperature ranges from 0xc2x0 C. to 60xc2x0 C.
When the protecting group is an alkyl ether, removal of such alkyl ether protecting groups is conducted using well known dealkylative conditions. For example, the alkyl ether may be cleaved by reaction with boron tribromide or diethylboron bromide in a reaction inert solvent, preferably a halocarbon solvent. It will be recognized by those skilled in the art that a buffer such as triethylamine may facilitate the reaction. The reaction times range from 15 minutes to 24 hours and the reaction temperature ranges from 0xc2x0 C. to 60xc2x0 C. In addition, a benzyl ether protecting group can be removed via standard or transfer hydrogenolysis using a palladium catalyst such as palladium on carbon. The hydrogenolysis reaction is conducted under a hydrogen atmosphere at ambient pressure to 50 psi in a reaction inert solvent, preferably methanol. The hydrogen source may be hydrogen gas, ammonium formate or trialkylammonium formate or cyclohexene. The reaction temperature ranges from room temperature to the reflux temperature of the solvent employed. The reaction time ranges from 15 minutes to 24 hours.
When a silyl ether protecting group is employed, removal of such silyl ether protecting groups is conducted under acidic conditions, preferably with aqueous hydrochloric acid such as 1 N to 6 N hydrochloric acid. The de-protection may be carried out in the presence of a co-solvent such as methanol or tetrahydrofuran. The reaction time ranges from 2 hours to 48 hours and the reaction temperature ranges from 0xc2x0 C. to 100xc2x0 C. Alternatively, the silyl ether protecting group may be removed via fluoride-mediated deprotection. In this case, deprotection is conducted using tetrabutylammonium fluoride or one of a variety of hydrofluoric acid sources in a reaction inert solvent. It is preferred to use ethereal solvents such as diethyl ether, dioxane or tetrahydrofuran, with tetrahydrofuran being especially preferred. The reaction time ranges from 2 hours to 48 hours and the reaction temperatures range from 0xc2x0 C. to the reflux temperature of the solvent being used. Other methods for removal of the aforementioned protecting groups are well known to those skilled in the art or can be found in Greene, T. W.; Wuts, P. G. M., Protective Groups in Organic Synthesis, 2nd ed.; John Wiley and Sons Inc.: New York, 1991. Other suitable hydroxyl protecting groups and methods for their removal may be found also be found therein. The method of Scheme I is preferred when R3 is R3k, l, m, n, o, p and q. Thus, compounds of formula 1-2 are reacted with compounds of formula 1-1. Compounds of formula 1-2 where R3 is R3k, l, m, n, o, p or q are commercially available or can be prepared by methods well known to those skilled in the art. 
Compounds of formula 2-7 are prepared as set forth in Scheme 2, particularly as described be low.
Where R27 is H, ethyl 1-benzyl-3-oxo-4-piperidine-carboxylate hydrochloride, the compound of formula 2-1, which is available from Aldrich, is condensed with compounds of formula 2-2 to give compounds of formula 2-3. The compounds of formula 2-1 where R27 is not H can be prepared according to methods well known to those skilled in the art. The reaction is conducted in the presence of excess base including non-aqueous bases, organic amines and inorganic bases. Preferred organic amines include triethylamine and pyridine. Preferred non-aqueous bases include alkaline metal (C1-C4)alkoxides. Preferred inorganic bases include potassium carbonate. The reaction is conducted in a reaction inert solvent. Preferred such solvents include (C1-C4)alcohols, aromatic or aliphatic hydrocarbons, polar aprotic solvents, halocarbons, and ethereal solvents. (C1-C4)Alcohols are especially preferred. The reaction time ranges from 2 hours to 3 days. The reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being employed. The reaction is preferably run at ambient pressure but may be conducted at pressures up to 250 psi.
Compounds of formula 2-4 are prepared from compounds of formula 2-3 by converting a compound of formula 2-3 into an activated compound of formula 2-4 where Lv1 is selected from fluoro, chloro, bromo, iodo, trifluoromethanesulfonate, (C1-C6)alkylsulfonate, or phenylsulfonate, wherein said phenyl is optionally substituted with up to three (C1-C4)alkyl, halo or nitro. This reaction is accomplished by reacting compounds of formula 2-3 with a chlorinating agent such as phosphorus oxychloride and/or phosphorus pentachloride to provide compounds of formula 2-4 where Lv1 is chloro. This reaction is conducted at ambient pressure in the absence of solvent or in a reaction inert solvent, preferably a halocarbon solvent at temperatures ranging from ambient temperature to 180xc2x0 C. Treatment of the chloro compound thus formed with the requisite mineral acid provides a compound of formula 2-4 where Lv1 is bromo or iodo. A sulfonate of formula 2-4 is prepared by reaction of a compound of formula 2-3 with a sulfonic acid chloride or anhydride in the presence of an organic amine base, preferably triethylamine or pyridine. In certain cases recognized by those skilled in the art, it may be necessary to add a catalyst to the reaction. In those cases, a preferred catalyst is 4-dimethylaminopyridine. This reaction is conducted at ambient pressure in a reaction inert solvent, preferably pyridine, a halocarbon such as chloroform, dichloromethane or carbon tetrachloride, an aromatic or aliphatic hydrocarbon, an ethereal solvent, or combinations thereof. The reaction temperature ranges from xe2x88x9220xc2x0 C. to 100xc2x0 C. and the reaction time ranges from 15 minutes to 1 day.
Compounds of formula 2-5 wherein R29 is defined above are prepared from compounds of formula 24 by a reduction reaction or by displacement of Lv1 with a nucleophile. The reduction is conducted with a reducing agent, preferably ammonium formate or hydrogen gas, in a reaction inert solvent. The reduction is conducted in the presence of a palladium catalyst at ambient pressure or under a hydrogen pressure of up to 50 psi. Preferred solvents include (C1-C4)alcohols such as methanol and ethanol, and ether solvents such as diethyl ether, dioxane and tetrahydrofuran. The nucleophilic displacement reaction may be conducted by adding the nucleophile directly or by pre-forming the nucleophile separately or in situ from a nucleophile precursor. Preferred nucleophiles include organoaluminum, organoboron, organocopper, organotin, organozinc or Grignard reagent; R29-H; or, where R29 contains a hydroxyl or thiol group, the anion of R29. The term xe2x80x9corganoxe2x80x9d in the terms organoaluminum, organoboron, organocopper, organotin and organozinc refers to an organic radical selected from R29. It will be recognized by those skilled in the art that transition-metal catalysts may be required to effect reaction in certain displacement reactions. When required, such transition metal catalysts may include palladium(0), palladium(II), nickel(0), and nickel(II) complexes. Palladium(II) bis(diphenylphosphinobutane) dichloride is a preferred such catalyst. Additionally, an aqueous or non-aqueous base may be required in the displacement reaction. Preferred such bases include sodium carbonate, sodium hydride, triethylamine and sodium tert-butoxide. The reaction is conducted at ambient pressure in a reaction inert solvent such as a halocarbon, an aromatic or aliphatic hydrocarbon, an ether or a polar aprotic solvent or a combination thereof. In certain cases, a (C1-C4)alcohol is used as a solvent or co-solvent. The reaction temperature ranges from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent employed. The reaction time ranges from 1 hour to 3 days.
Compounds of formula 2-6 are prepared by removal of the benzyl protecting group from compounds of formula 2-3 or 2-5. This transformation is accomplished using the freebase, or preferably the pre-formed hydrochloride or similar salt, under standard or transfer hydrogenolysis conditions. The catalysts which may be used in the hydrogenolysis reaction include, but are not limited to, palladium on carbon, palladium hydroxide on carbon and platinum(IV) oxide. The reaction is conducted in a reaction inert solvent, preferably methanol or ethanol and the reaction temperature ranges from room temperature to the reflux temperature of the solvent being employed. The hydrogen source is hydrogen gas, ammonium formate, trialkylammonium formate, or cyclohexene. The reaction time ranges from minutes to 3 days. Generally the reaction is conducted at ambient pressure but pressures of up to 50 psi of hydrogen may be employed. Alternatively, if appropriate, the benzyl protecting group is removed in two steps via chloroformate-induced acylative dealkylation. This involves reaction with a chloroformate derivative to form a carbamate followed by cleavage of the carbamate. While this reaction is preferably conducted with 1-chloroethyl chloroformate and sodium iodide catalysis, it will be recognized by those skilled in the art that catalysis may not be required in certain cases. The reaction is conducted at ambient temperature in a reaction inert solvent such as a halocarbon, an aromatic or aliphatic hydrocarbon, a ketone, an ether or a polar aprotic solvent. The reaction temperature ranges from xe2x88x9278xc2x0 C. to the reflux temperature of the solvent being employed and the reaction time ranges from 15 minutes to 1 day. Cleavage of the carbamate formed by reaction with 1-chloroethyl chloroformate is accomplished upon exposure to methanol or ethanol at ambient pressure to give compounds of formula 2-6 as a hydrochloride salt. The reaction proceeds at temperatures from room temperature to the reflux temperature of the solvent being employed and the reaction time ranges from 15 minutes to 1 day. Deprotection conditions for other carbamates can be found in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; John Wiley and Sons Inc.: New York, 1991, pp 315-348.
Compounds of formula 2-7 are prepared from the displacement reaction of amine 2-6 as described in Scheme 1, where the amine 2-6 is equivalent to R3xe2x80x94NH.
Alternatively, compounds of formula 2-7 where R29 is as defined above are prepared from compounds of formula 2-3 wherein R29 is OH according to the sequence outlined in Scheme 2a below, wherein the conditions are as set forth as described for Scheme 2. 
Compounds of formula 2-2 which are used in Schemes 2 and 2a above are commercially available or are prepared according to methods well known to those 5 skilled in the art, such as those described in March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley and Sons.: New York, 1985, p 359, 374. 
Compounds of formula 3-5 are prepared as set forth in Scheme 3 above and more particularly as described below.
Compounds of formula 3-3 are prepared by condensing a compound of formula 3-1 with a compound of formula 3-2. Where R38 and R39 are each H, the compound of formula 3-1 is 1-benzyl-4-piperidone, which is commercially available from Aldrich. Compounds of formula 3-2 are either commercially available or can be prepared according to methods well known to those skilled in the art, particularly according to methods set forth in March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley and Sons Inc.: New York, 1985, pp 499-500. The reaction is conducted at ambient pressure in the presence of a secondary amine. Generally an excess of the secondary amine, preferably pyrrolidine, piperidine, morpholine or diethylamine, is used. An especially preferred secondary amine is pyrrolidine. The reaction is conducted in a reaction inert solvent, preferably a (C1-C4)alcohol, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon or an ether. An especially preferred solvent is ethanol. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being employed.
Compounds of the formula 3-4 are prepared by removal of the benzyl protecting group from compounds of formula 3-3. This transformation is conducted in a manner analogous to the procedure set forth for the preparation of compounds of formula 2-6 above.
Compounds of formula 3-5 are prepared from the displacement reaction of amine 3-4 as described in Scheme 1, where the amine 34 is equivalent to R3xe2x80x94NH. 
Compounds of formulas 3a-1 and 3a-2 are prepared as shown in Scheme 3a from compounds of formula 3-5. Thus, to prepare a compound of 3a-1, a compound of formula 3-5 is reduced with a common reducing agent, such as, for example, sodium borohydride, lithium aluminum hydride or diisobutylaluminum hydride. Other reducing agents capable of effecting the reduction of a ketone to an alcohol are well known to those skilled in the art (e.g., Larock, R. D. Comprehensive Organic Transformations, VCH Publishers, Inc.: New York, 1989, pp 527-547). Likewise, compounds of formula 3a-2 are prepared from compounds of formula 3-5 by reduction with reducing agents capable of reducing a ketone completely to a methylene group. A preferred such reducing agent is aluminum trichloride/borane-tert-butylamine complex. Other such reducing agents are well known to those skilled in the art (e.g., J. Org. Chem. 1989, 54, 4350; Larock, R. D. Comprehensive Organic Transformations, VCH Publishers, Inc.: New York, 1989, pp 35-37). It will be recognized by those skilled in the art that the transformation of 3-5 to 3a-1 or 3a-2 can be conducted at different points in Scheme 3, depending upon the dynamics of the particular system.
Alternatively, compounds of formula 3-5 wherein R38 and R39 are hydrogen can be prepared from 4-piperidone monohydrate monochloride in a manner analogous to the procedure described in Scheme 1, where the amine 3-6 is equivalent to R3xe2x80x94NH to give compounds of formula 3-7. Compounds of formula 3-7 can be reacted with compounds of formula 3-2 in a manner analogous to the procedure set forth for the synthesis of compounds of formula 3-3 to afford compounds of formula 3-5. 
Compounds of formula 4-5 are prepared according to Scheme 4 and more particularly as described below.
Compounds of formula 4-3 are prepared by reacting a compound of formula 4-2 with a compound of formula 4-1 or 4-1a. Compounds of formula 4-1 and 4-1 a are prepared according to methods well known to those skilled in the art. Where R32 is hydrogen, 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester is condensed with a compound of formula 4-2 to afford a compound of formula 4-3. Said compounds of formula 4-2 are readily available from well known commercial vendors, known in the literature, or are synthesized under standard conditions well known to those skilled in the art. Preferred conditions to prepare compounds of formula 4-3 from a compound of formula 4-1 where A is CO and B is NH or from a compound of formula 4-1a where A is NH and B is CO can be found in March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley and Sons Inc.: New York, 1985, p 1163. The reaction is conducted at ambient pressure in a reaction inert solvent. Preferred such solvents include aqueous media, a (C1-C4)alcohol, glacial acetic acid, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and ethers or combinations thereof. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being used. An optional second step using aqueous or non-aqueous base may be employed in certain cases which will be recognized by those skilled in the art. This second step is conducted at ambient pressure in a reaction inert solvent. Preferred such solvents include aqueous media, a (C1-C4)alcohol, glacial acetic acid, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and ethers or combinations thereof. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being used.
Compounds of formula 4-3 wherein B is CO and A is N-alkyl or wherein B is N-alkyl and A is CO are prepared by alkylation of compounds of formula 4-3 where B is CO and A is NH or wherein B is NH and A is CO, respectively. The anion of those compounds of formula 4-3 is formed by reaction with an appropriate base. Preferred such bases include sodium hydride and sodium hexamethyldisilazide, although other bases may be used where conditions warrant, as determined by the skilled person. The reaction is conducted in a reaction inert solvent, preferably an ether such as tetrahydrofuran, diethyl ether, dioxane or diglyme or polar aprotic solvent such as dimethylformamide. The reaction proceeds at ambient pressure and at temperatures ranging from xe2x88x92100xc2x0 C. to ambient temperature. The reaction times are from 10 minutes to 2 hours. Addition of (C1-C4)alkyl halides or (C1-C4)alkylsulfonates such as mesylate, tosylate or nosylate to the anion of 4-3 proceeds at ambient pressure and at temperatures ranging from xe2x88x9220xc2x0 C. to 50xc2x0 C. The reaction times range from 10 minutes to 1 day.
Compounds of formula 4-4 are prepared form compounds of formula 4-3 wherein A is N-alkyl and B is CO or A is CO and B is N-alkyl via acid-catalyzed deprotection of the Boc carbamate under standard conditions, for example, hydrochloric acid or trifluoroacetic acid in a reaction inert solvent or in the absence of solvent. Such conditions are known to those skilled in the art. Exemplary conditions are disclosed in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; John Wiley and Sons Inc.: New York, 1991, pp 327-330.
Compounds of formula 4-5 are prepared by the displacement reaction of amine 4-4 as described in Scheme 1, where the amine 4-4 is equivalent to R3xe2x80x94H. 
Compounds of formula 5-4 where X is a covalent bond and G, G1, G2, q, R1, R2, R6, R7 and R8 are as defined above are prepared according to Scheme 5 above and particularly as described below.
Compounds of formula 5-3 are prepared by reaction of a compound of formula 5-1 with a compound of formula 5-2 where Prt is an optional amine protecting group selected from benzyl and CO2R90, where R90 is selected from (C1-C4)alkyl, (C1-C4)allyl, trichloroethyl and benzyl substitutedby up to two (C1-C4)alkoxy. Compounds of formula 5-1 where R9 is Ar1 and Lv3 is halo, (C1-C4)alkylsulfide, (C1-C4)alkylsulfone, trifluoromethanesulfonate, (C1-C6)alkylsulfonate or phenylsulfonate, where said phenyl is optionally substituted with up to three halo, nitro or (C1-C4)alkyl are commercially available or are readily prepared according to methods well known to those skilled in the art. For example, to prepare compounds of formula 5-1 wherein Lv3 is chloro, a compound of formula Ar1xe2x80x94OH, or the Ar1xe2x80x94(xe2x95x90O) tautomer thereof, is reacted with a chlorinating agent such as phosphorus oxychloride and/or phosphorus pentachloride. This chlorinating reaction is conducted at ambient pressure in the absence of solvent or in a reaction inert solvent, preferably a halocarbon solvent, at temperatures ranging from ambient temperature to 180xc2x0 C. Treatment of the chloro compound with the requisite mineral acid provides compounds of formula 5-1 where Lv3 is bromo or iodo. Compounds of formula 5-1 wherein Lv3 is trifluoromethanesulfonate, (C1-C6)alkylsulfonate or phenylsulfonate are prepared from a compound of formula Ar1xe2x80x94OH, or the Ar1xe2x80x94(xe2x95x90O) tautomer thereof, by reaction with a sulfonic acid chloride or anhydride in the presence of a base, preferably an organic amine such as triethylamine, N,Nxe2x80x2-diisopropylethylamine, dimethylaminopyridine or pyridine. In certain cases it will be recognized by those skilled in the art that a catalyst will be required to effect reaction. In those cases, a preferred catalyst is 4-dimethylaminopyridine. This reaction is conducted at ambient pressure in a reaction inert solvent such as pyridine, a halocarbon, an aromatic or aliphatic hydrocarbon, an ether, or a combination thereof. The reaction temperature ranges from xe2x88x9220xc2x0 C. to 100xc2x0 C. and the reaction time ranges from 15 minutes to 1 day. Compounds of formula 5-1where Lv3 is thiomethyl are prepared by reacting a compound of formula Ar1xe2x80x94SH, or the Ar1xe2x80x94(xe2x95x90S) tautomer thereof, with methyl iodide or dimethylsulfate in the presence of an inorganic base, preferably potassium carbonate. These reactions are conducted at ambient pressure in a reaction inert solvent, preferably an ether or a polar aprotic solvent. An especially preferred polar aprotic solvent is dimethylformamide at a temperature ranging from 0xc2x0 C. to 100xc2x0 C. Compounds of formula 5-1 where Lv3 is methylsulfone are prepared from a compound of formula 5-1 where Lv3 is thiomethyl by oxidation thereof according to procedures well known to those skilled in the art, specifically as set forth in March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley and Sons.: New York, 1985, pp 1089-1090.
A representative set of compounds of formula 5-1 which are commercially available or which can be prepared according to methods analogous to a literature procedure include 4-chloropyridine (Aldrich, P.O. Box 355, Milwaukee, Wis. 53201, USA), 3-chloro-6-methyl-pyridazine (Maybridge, c/o Ryan Scientific, 443 Long Point Road, Suite D, Mount Pleasant, S.C. 29464, USA), 2-chloro-pyrazine (Aldrich), 2,6-dichloro-pyrazine (Aldrich), 3-chloro-2,5-dimethylpyrazine (Aldrich), 2,4-dichloro-pyrimidine (Aldrich), 4,6-dichloro-pyrimidine (Aldrich), 4-chloro-2-methyl-pyrimidine (Chem. Ber. 1904, 37, 3641), 4-chloro-6-methyl-pyrimidine (Chem. Ber. 1899, 32, 2931), 4-chloro-2,6-dimethyl-pyrimidine (J. Am. Chem. Soc. 1946, 68, 1299), 4-chloro-2,6-bis(trifluoromethyl)-pyrimidine (J. Org. Chem. 1961, 26, 4504), 4-chloro-2-methylsulfanyl-pyrimidine (Aldrich), 4-chloro-2-methoxymethyl-pyrimidine (U.S. Pat. No. 5,215,990), 1-chloro-isoquinoline (J. Am. Chem. Soc. 1946, 68, 1299), 2-chloro-quinoline (Aldrich), 4-chloro-quinazoline (J. Am. Chem. Soc. 1909, 31, 509), 2-chloro-quinoxaline (U.S. Pat. No. 2,537,870), 2-chloro-3-methyl-quinoxaline (Aldrich), 2,6,7-trichloro-quinoxaline (J. Chem. Soc., Chem. Commun. 1956, 4731), 4-chloro-pteridine (J. Chem. Soc., Chem. Commun. 1954, 3832), 7-chloro-pteridine (J. Chem. Soc., Chem. Commun. 1954, 3832), and 6-chloro-9H-purine (Aldrich). Other compounds of formula 5-1 can be prepared using methods well known to those skilled in the art or by using methods analogous to those described in the foregoing references.
Compounds of formula 5-3 are prepared by the displacement reaction of a compound of formula 5-1 with an amine of the formula 5-2. The reaction is conducted in the presence of a non-aqueous base, prefeably an organic amine such as pyridine, 4-dimethylaminopyridine, triethylamine or N,Nxe2x80x2-diisopropylethylamine; an inorganic base such as potassium or sodium carbonate or bicarbonate; or an alkaline metal alkoxide such as potassium t-butoxide. Alternatively, an excess of the reacting amine 5-2 can be used in lieu of the added base. In cases where the leaving group Lv3 is unactivated, or in specific cases which will be recognized by those skilled in the art, the use of a transition-metal catalyst such as palladium(0), palladium (II), nickel(0) or nickel(II), along with phosphine-based ligands, such as 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (BINAP), may be required to effect reaction. More specific details concerning this reaction are available in the following references: J. Org. Chem. 1997, 62, 1264; J. Org. Chem. 1997, 62, 1568; SynLett 1997, 329. The reaction can be conducted in the absence of solvent or in a reaction inert solvent. Preferable reaction inert solvents include aqueous media, (C1-C4)alcohol, (C2-C6)glycol, a halocarbon, an aliphatic or aromatic hydrocarbon, an ether, a polar aprotic solvent, a ketone, or combinations thereof. The reaction time ranges from 15 minutes to 3 days and the reaction temperature ranges from 0xc2x0 C. to 180xc2x0 C. or to the reflux temperature of the solvent being used. The reactions are preferably conducted at ambient pressure.
In certain cases which will be recognized by those skilled in the art, transformations of existing functionality in Ar1 of compound 5-3 may be necessary to produce compounds of formula 54. This pertains in particular to those cases where, for example, R9 in 5-3 contains an aromatic or heteroaromatic halide, (C1-C4)alkylsulfonate or triflate. Said compounds of formula 5-3 wherein Ar1 contains up to two substituents selected from halide, (C1-C4)alkylsulfonate or triflate, may be converted to a compound of formula Ar1 where said halide, (C1-C4)alkylsulfonate or triflate is transformed into another functional group by a reduction reaction or by a displacement reaction of said halide, (C1-C4)alkylsulfonate or triflate with a nucleophile. The reduction reaction is conducted with a reducing agent, preferably in ammonium formate or hydrogen gas, in a reaction inert solvent. The reduction is conducted in the presence of a palladium catalyst at ambient pressure or under a hydrogen pressure of up to 50 psi. Preferred solvents include (C1-C4)alcohols such as methanol and ethanol, and ether solvents such as diethyl ether, dioxane and tetrahydrofuran. The nucleophilic displacement reaction may be conducted by adding the nucleophile directly or by pre-forming the nucleophile separately or in situ from a nucleophile precursor. Preferred nucleophiles include organoaluminum, organoboron, organocopper, organotin, organozinc or Grignard reagent; R11-oxide or R11-thioxide; or anilino where anilino is within the scope of R11. It will be recognized by those skilled in the art that transition-metal catalysts may be required to effect reaction in certain displacement reactions. When required, such transition metal catalysts may include palladium(0), palladium(II), nickel(0), and nickel(II) complexes. Palladium(II) bis(diphenylphosphinobutane) dichloride is a preferred such catalyst. Additionally, an aqueous or non-aqueous base may be required in the displacement reaction. Preferred such bases include sodium carbonate, sodium hydride, triethylamine and sodium tert-butoxide. The reaction is conducted at ambient pressure in a reaction inert solvent such as a halocarbon, an aromatic or aliphatic hydrocarbon, an ether or a polar aprotic solvent or a combination thereof. In certain cases, a (C1-C4)alcohol is used as a solvent or co-solvent. The reaction temperature ranges from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent employed. The reaction time ranges from 1hour to 3 days.
Optional protecting groups which may be present in compounds of formula 5-3 are removed according to methods set forth above, or according to methods well known to those skilled in the art, particularly as set forth in: Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; John Wiley and Sons Inc.: New York, 1991.
Compounds of formula 5-4 are prepared from the displacement reaction of amine 5-3 as described in Scheme 1, where the amine 5-3 is equivalent to R3xe2x80x94NH. A representative set of amines of formula 5-3 which are commercially available or which can be prepared by a literature procedure include 1-phenyl-piperazine (Aldrich), 1-pyridin-2-yl-piperazine (Aldrich), 3-piperazin-1-yl-benzo[d]isoxazole (J. Med. Chem. 1986, 29, 359), 3-piperazin-1-yl-benzo[d]isothiazole (J. Med. Chem. 1986, 29, 359), 2-piperazin-1-yl-quinoxaline (J. Med. Chem. 1981, 24, 93), 1-naphthalen-2-yl-piperazine (cf. Tetrahedron Lett. 1994, 35, 7331), and 1-(3,5-dimethylphenyl)-piperazine (cf. Tetrahedron Lett. 1994, 35, 7331). Other compounds of formula 5-3 can be prepared using methods well known to those skilled in the art or by using methods analogous to those described in the foregoing references.
Alternatively, compounds of formula 5-4 can be prepared from reaction with compounds of formula 5-1with compounds of formula 5-5 using conditions set forth above to prepare 5-3. Compounds of formula 5-5 can be prepared in a manner analogous to the method used to prepare compounds of formula 1-3.
Compounds of formula 54 wherein X is oxycarbonyl, vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl, thio(C1-C4)alkenylcarbonyl, vinylenylsulfonyl or carbonyl(C0-C4)alkylenylcarbonyl; wherein said oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl, and thio(C3-C4)alkenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C1-C4)alkyl, benzyl, or Ar; said vinylenylsulfonyl and said vinylenylcarbonyl in the definition of X are each optionally and independently substituted with up to three (C1-C4)alkyl, benzyl, or Ar are also prepared according to Scheme 5 above and particularly as described below.
Compounds of formula 5-4 where X is as defined in the immediately preceding paragraph are prepared by reacting a compound of formula 5-5 with a compound of formula 5-1where R9 is described above, X is as defined in the immediately preceding paragraph and Lv3 is chloro. The reaction is conducted under anhydrous conditions in the presence of a non-aqueous base, which includes organic amines such as triethylamine, N,Nxe2x80x2-diisopropylethylamine and pyridine and derivatives thereof. The reaction is generally conducted in a reaction inert solvent. Preferred solvents include halocarbon, aliphatic or aromatic hydrocarbon, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from 0xc2x0 C. to 80xc2x0 C. or to the reflux temperature of the solvent being used. The reactions are preferably conducted at from 0xc2x0 C. to ambient temperature and at ambient pressure. Removal of optional protecting groups is carried out as described in Scheme I.
Compounds of formula 5-4 wherein X is vinylenylcarbonyl, oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl, thio(C2-C4)alkenylcarbonyl, or carbonyl(C0-C4)alkylenylcarbonyl,; wherein said oxy(C1-C4)alkylenylcarbonyl, (C1-C4)alkylenylcarbonyl, (C3-C4)alkenylcarbonyl, and thio(C2-C4)alkenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C1-C4)alkyl, benzyl, or Ar; and said vinylenylcarbonyl in the definition of X are each optionally and independently substituted with up to three (C1-C4)alkyl, benzyl, or Ar are also prepared according to Scheme 5 avove and particularly as described below.
Compounds of formula 5-4 are prepared by reacting a compound of formula 5-5 with a compound of formula R9xe2x80x94Xxe2x80x94Lv3 where R9 is described above, X is as defined in the immediately preceding paragraph and Lv3 is OH. The reaction is conducted in the presence of coupling agents, preferably dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as described in J. Amer. Chem. Soc. 1996, 118, 4952. The reaction is conducted in a reaction inert solvent. Preferred solvents include halocarbon, aliphatic or aromatic hydrocarbon and ethers. Especially preferred solvents include dichloromethane and chloroform. Other coupling agents that can be used are well known to those skilled in the art and include, but are not limited to, various phosphine reagents, ethyl chloroformate, and N-hydroxysuccinimide. These reagents and procedures are described in xe2x80x9cCompendium of Organic Synthetic Methodsxe2x80x9d (Ed., I. T. Harrison and S. Harrison, John Wiley and Sons). Specific references include the following: J. Org. Chem, 1971, 36,1305; Bull. Soc. Chim. Fr., 1971, 3034; Bull. Chem. Soc. Japan, 1971, 44, 1373; Tetrahedron Lett., 1973, 28, 1595; Tetrahedron Lett., 1971, 26, 2967, and J. Med. Chem., 1968, 11, 534. Removal of optional protecting groups is carried out as described in Scheme I.
Compounds of formula 5-4 wherein X is a covalent bond and R9 is (C3-C7)cycloalkyl or Ar1xe2x80x94(C1-C3)alkylenyl are also prepared according to Scheme 5 above and particularly as described below.
Compounds of formula 54 wherein X is a covalent bond and R9 is (C3-C7)cycloalkyl or Ar1xe2x80x94(C1-C3)alkylenyl are prepared by reacting a compound of formula 5-1wherein X is a covalent bond, R9 is (C3-C7)cycloalkyl or Ar1xe2x80x94(C1-C3)alkylenyl and Lv3 is halo, methanesulfonate, p-toluenesulfonate or trifluoromethanesulfonate. The reaction is conducted under anhydrous conditions in the presence of a non-aqueous base, which includes organic amines such as triethylamine, N,Nxe2x80x2-diisopropylethylamine and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent. Preferred solvents for the reaction include halocarbons, aliphatic or aromatic hydrocarbons, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from xe2x88x9220xc2x0 C. to 80xc2x0 C. or to the reflux temperature of the solvent being used. The reactions are preferably conducted at ambient temperature of the solvent being used and at ambient pressure. Removal of optional protecting groups is conducted as set forth in Scheme I. 
Compounds of formula 6-5 wherein G, G1, G2, q, R1, R2, R6, R7 and R8 are as defined above are prepared as set forth in Scheme 6 above and particularly as described below.
Compounds of formula 6-1 are prepared from an amine of the formula 5-2 where Prt is an optional amine protecting group selected from benzyl and CO2R90, where R90 is selected from (C1-C4)alkyl, (C1-C4)allyl, trichloroethyl and benzyl substituted with up to two (C1-C4)alkoxy. The preferred procedure for preparing compounds of formula 6-1can be found in Tetrahedron Lett. 1993, 48, 7767 or J. Org. Chem 1997, 62, 1540.
Compounds of formula 6-3 are prepared by condensation of xcex2-diketones or xcex2-ketoesters of the formula 6-2b, where R11 and R12 are independently substituted as set forth above, or compounds of the formula 6-2a where Lv4 is, for example, hydroxy, chloro or dimethylamino with guanidines of the formula 6-1. The reaction is conducted in the presence of an aqueous or non-aqueous base, preferably potassium or sodium hydroxide, potassium or sodium (C1-C4)-alkoxide, triethylamine, pyridine, 4-dimethylaminopyridine, potassium or sodium carbonate or potassium or sodium bicarbonate. The reaction is conducted in a reaction inert solvent, preferably aqueous media, a (C1-C4)alcohol, a (C2-C6)dialcohol, an aromatic hydrocarbon, a polar aprotic solvent, or combinations thereof. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from room temperature to reflux of the solvent employed. The reaction is preferably run at ambient pressure, but may be conducted at pressures up to 250 psi.
Removal of of optional protecting groups in compounds of formula 6-3 to afford compounds of formula 6-4 is accomplished as set forth above.
Compounds of formula 6-5 are prepared from the displacement reaction of amine 64 as described in Scheme 1, where the amine 6-4 is equivalent to R3xe2x80x94NH.
Alternatively, compounds of formula 6-5 are prepared from compounds of formula 5-5 by formation of a compound of formula 6-6, or by reaction with compounds of formula 6-2a or 6-2b under the conditions outlined above in Scheme 6. Removal of optional protecting groups is conducted as described in Scheme 1. Compounds of formula 5-5 are prepared as set forth above. 
Compounds of formula 7-4 wherein G3, G4, G5, r, R1, R2, R18, R19 and R20 are defined as set forth above are prepared as set forth in Scheme 7 and particularly as described below.
Compounds of formula 7-1 are prepared by reaction of an amine of the formula 7-0 with phosgene or a phosgene equivalent such as triphosgene. Compounds of 7-1 wherein the chloro group is replaced by an imidazolyl group are also useful in this reaction. Such compounds are prepared by reaction of an amine of formula 7-0 with carbonyl diimidazole. The reaction is conducted under anhydrous conditions in the presence of a nonaqueous base. Preferred such bases include triethylamine and other tertiary amines and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent at xe2x88x9278xc2x0 C. to 80xc2x0 C. or at the reflux temperature of the solvent being used for 15 minutes to 24 hours. Preferred solvents for this reaction include a halocarbon, an aliphatic or aromatic hydrocarbon, an ether, ethyl acetate, pyridine and combinations thereof. The reactions are preferably conducted at from 0xc2x0 C. to ambient temperature and at ambient pressure.
Compounds of formula 7-4 are prepared by reaction of carbamoyl chlorides of the formula 7-1with amines of the formula 7-3, where R21 and R22 are defined above. The reaction can be conducted in the absence of solvent, or in a reaction inert solvent. Preferred such solvents include aqueous media, a (C1-C4)alcohol, a (C2-C6)dialcohol, an aromatic or aliphatic hydrocarbon, a halocarbon, an ether, a polar aprotic solvent, a ketone, pyridine or combinations thereof. The reaction time ranges from 15 minutes to 3 days and the reaction temperature ranges from 0xc2x0 C. to the reflux temperature of the solvent being used. The reaction is preferably conducted at ambient pressure. It will be recognized by those skilled in the art that addition of a base may be required to effect reaction. In those cases, preferred bases include potassium or sodium hydroxide, triethylamine and other tertiary amines, pyridine and its derivatives and inorganic bases such as sodium or potassium carbonate and sodium or potassium bicarbonate. Removal of optional hydroxyl protecting groups contained in R1 is carried out according to methods set forth in Scheme 1.
Alternatively, compounds of formula 7-4 are prepared from compounds of formula 7-0 by reaction with isocyanates of the formula 7-6 or with carbamoyl chlorides of the formula 7-8. Said isocyanates are commercially available, known in the literature, or synthesized under standard conditions known to those skilled in the art, particularly as described in March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley and Sons Inc.: New York, 1985, p 1166. A preferred method of forming such isocyanates is the Curtius rearrangement of a suitable acyl azide. Said carbamoyl chlorides are synthesized using methods analogous to that described for the preparation of compounds of formula 7-1in Scheme 7. Removal of optional hydroxyl protecting groups contained in R1 is carried out according to methods set forth in Scheme 1.
Compounds of formula I containing the radical R3c are prepared according to the procedures set forth in Scheme 7 using the corresponding starting materials and reagents. 
Compounds of formula 8-5 are prepared as set forth in Scheme 8 and particularly as described below.
Compounds of formula 8-2 are readily prepared from commercially available phenethylamines of formula 8-1a and formaldehyde or an aldehyde of the formula R27xe2x80x94CHO under Pictet-Spengler conditions. The Pictet-Spengler reaction is reviewed in Chem. Rev. 1995, 95, 1797. A similar route route to 1,2,3,4-tetrahydroisoquinolines using the Bischler-Napieralski reaction, as disclosed in March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley and Sons.: New York, 1985, 495, followed by standard reduction of the imine formed may also be employed.
Compounds of formula 8-4 are prepared from compounds of formula 8-3 by aromatic electrophilic substitution using the appropriate electrophile. A general reference for this type of reaction can be found in March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley and Sons.: New York, 1985, 447-511.
Compounds of formula 8-2 are also prepared by removal of the protecting group from a compound of formula 8-4. Preferably the protecting group is trifluoroacetamide which may be removed under basic conditions using inorganic hydroxides or carbonates in a reaction inert solvent. Suitable such solvents include (C1-C4)alcohols and preferably methanol. Optionally, one or more co-solvents, preferably selected from water, tetrahydrofuran and dioxane may be employed. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from 0xc2x0 C. to 100xc2x0 C. or to the reflux temperature of the solvent or solvent system being used. The reaction is preferably conducted at ambient temperature. Other conditions for deprotection of trifluoroacetamides and deprotection conditions for other suitable protecting groups can be found in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; John Wiley and Sons Inc.: New York, 1991.
Compounds of formula 8-4 are prepared by adding a protecting group to compounds of formula 8-2. Preferably the protecting group is trifluoroacetamide or tert-butoxycarbonyl (BOC). The protecting group is attached by reaction of a compound of formula 8-2 with trifluoroacetyl chloride or di-tert-butyl dicarbonate or an equivalent thereof in the presence of a base, preferably triethylamine or pyridine. The reaction is conducted in a reaction inert solvent. Preferred such solvents include ethers such as tetrahydrofuran, diethyl ether, dioxane or dimethoxyethane; a halocarbon such as dichloromethane, chloroform or carbon tetrachloride; and aromatic or aliphatic hydrocarbons such as benzene, toluene or hexanes. The reaction time ranges from 15 minutes to 3 days and the reaction temperature ranges from 0xc2x0 C. to the reflux temperature of the solvent being used. The reaction is preferably conducted at ambient pressure. Other conditions for protection of amines with trifluoroacetamides or tert-butoxycarbonyl groups as well as other suitable protecting groups can be found in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; John Wiley and Sons Inc.: New York, 1991.
Manipulation of the substituents R28 and R29 is carried out to provide isoquinolines with altered substitution. Preferably, transition metal-catalyzed cross-coupling of a compound of formula 8-4 where R28 or R29 is bromide or triflate is employed to afford compounds of formula 8-4 wherein R28 or R29 are as set forth above. This reaction is conducted according to methods well known to those skilled in the art, particularly as set forth in Tetrahedron, 1998, 54, 263 for Stille and Suzuki Reactions and in Acc. Chem. Res. 1998, 31, 805 for Buchwald Amination Reactions.
Compounds of formula 8-5 are prepared from the displacement reaction of amine 8-2 as described in Scheme 1, where the amine 8-2 is equivalent to R3xe2x80x94NH. 
Compounds of formula 9-3 are prepared according to the general procedures set forth in Scheme 2 starting from ethyl 1-benzyl-4-oxo-3-piperidine carboxylate hydrochloride (9-1). In certain cases, where R29 is H, N-tertbutoxycarbonyl-3-(dimethylaminomethylene)-4-piperidone (9-2, Chemical Abstracts 121:157661) is used as the starting material. 
Compounds of formula 10-6 wherein R1, R2, R32 and R33 are as defined above are prepared as set forth in Scheme 10 and more particularly as described below.
Compounds of formula 10-2 where R91 is (C1-C4)alkyl are prepared by reacting a compound of formula 10-1, where Cbz is benzyloxycarbonyl, with an O-alkylating agent. A preferred compound of formula 10-1 is 3-oxo-piperazine-1-carboxylic acid benzyl ester. A preferred O-alkylating agent is triethyloxonium tetrafluoroborate. The reaction is conducted at ambient pressure in a reaction inert solvent. Preferred solvents include an aromatic or aliphatic hydrocarbons, halocarbons and ethers. Dichloromethane is especially preferred. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from xe2x88x92100xc2x0 C. to ambient temperature.
Compounds of formula 10-4 are prepared by condensation of a compound of formula 10-2 with a compound of formula 10-3. Said compounds of formula 10-3 are commercially available, are known in the literature, or are readily prepared via standard amidation of hydrazine and an activated carboxylic acid, such as a carboxylic acid chloride. Such reactions are well known by those skilled in the art. The condensation reaction is preferably run at ambient pressure, although higher pressures up to 250 psi may be employed if necessary. The reaction is conducted in a reaction inert solvent, preferably selected from (C1-C4)alcohols, aromatic or aliphatic hydrocarbons, polar aprotic media, halocarbons and ethers, or combinations thereof. The reaction is conducted at temperatures ranging from ambient temperature to 180xc2x0 C. The reaction times are from 2 hours to 3 days.
Compounds of formula 10-5 are prepared form compounds of formula 10-4 via Lewis acid-catalyzed cleavage or hydrogenolysis of the Cbz carbamate under standard conditions which are well known to those skilled in the art, particularly as set forth in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; John Wiley and Sons Inc.: New York, 1991, pp 335-338.
Compounds of formula 10-6 are prepared from the displacement reaction of an amine of the formula 10-5 as described in Scheme 1, where the amine 10-5 is equivalent to R3xe2x80x94NH. 
Compounds of formula 11-4, wherein R1, R2, R36, R37, R38, R39 and R40 areas defined above are prepared as set forth in Scheme 11 and more particularly as described below.
Where R38 and R39 are hydrogen, 1-benzyl-4-piperidone (3-1), available from Aldrich, is condensed with a compound of formula 11-1, which are either commercially available or well known to those skilled in the art, to give compounds of formula 11-2. Where R38 and R39 are not hydrogen, compounds of formula 3-1 can be prepared according to methods well known to those skilled in the art. The reaction is conducted at ambient pressure in the absence of solvent or in a reaction inert solvent. Preferred solvents include (C1-C4)alcohols, aromatic or aliphatic hydrocarbons, polar aprotic solvents, halocarbons and ethers. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being employed. More specific conditions can be found in Indian J. Chem. 1976, 14B, 984 and J. Chem. Soc., Perkin Trans. 1 1984, 2465.
Compounds of formula 11-3 are prepared by removal of the benzyl protecting group from a compound of formula 11-2 in a manner analogous to the method employed for the preparation of compounds of 2-6 described above.
Compounds of formula 11-4 are prepared by the displacement reaction of an amine of the formula 11-3 as described in Scheme 1, where the amine 11-3 is equivalent to R3-H. 
Compounds of formula 12-3 and 12-3a where R17 and R23 are (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, Ar2-carbonyl, (C1-C6)alkylsulfonyl, Ar2-sulfonyl, or Ar2-sulfinyl are prepared according to Scheme 12 above and particularly as set forth below.
Compounds of formula 12-3 and 12-3a where R17 and R23 are as defined in the immediately preceding paragraph are prepared by condensation with a compound of formula 12-2 and 12-2a, wherein Lv4 is chloro, respectively. Examples of compounds of formula 12-2 and 12-2a include (C1-C6)alkoxyCOCl, (C1-C6)alkylCOCl, Ar2xe2x80x94SOCl, (C1-C6)alkylSO2Cl, Ar2xe2x80x94SO2Cl, or Ar2xe2x80x94SOCl. The reaction is conducted under anhydrous conditions in the presence of a non-aqueous base, which includes organic amines such as triethylamine, N,Nxe2x80x2-diisopropylethylamine and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent. Preferred solvents for the reaction include halocarbon, aliphatic or aromatic hydrocarbon, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from 0xc2x0 C. to 80xc2x0 C. or to the reflux temperature of the solvent being used. The reactions are preferably conducted at from 0xc2x0 C. to ambient temperature and at ambient pressure. Removal of optional protecting groups is carried out as described in Scheme I.
Compounds of formula 12-3 and 12-3a wherein R17 and R23 are (C1-C6)alkylcarbonyl or Ar2-carbonyl are also prepared according to Scheme 12 above and particularly as described below.
Compounds of formula 12-3 and 12-3a wherein R17 and R23 are (C1-C6)alkylcarbonyl or Ar2-carbonyl are prepared by a condensation reaction with a compound of formula 12-2 or 12-2a, respectively, wherein Lv4 is hydroxy in the presence of coupling agents such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction is conducted in a reaction inert solvent. Preferred solvents include halocarbon, aliphatic/aromatic hydrocarbons and ethers. Especially preferred solvents include dichloromethane and chloroform. Other coupling agents that can be used are well known to those skilled in the art and include, but are not limited to, various phosphine reagents, ethyl chloroformate, and N-hydroxysuccinimide. Removal of optional protecting groups is carried out as described in Scheme I.
Compounds of formula 12-3 where R17 is (C1-C6)alkyyl are also prepared according to Scheme 12 and particularly as described below.
Compounds of formula 12-3 where R17 is (C1-C6)alkyl are prepared by reacting a compound of formula 12-1 with a compound of formula 12-2 where R17 is (C1-C4)alkyl and Lv4 is Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy. The reaction is conducted under anhydrous conditions in the presence of a nonaqueous base, which includes organic amines such as triethylamine, Hunig""s base and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent. Preferred solvents for the reaction include halocarbons, aliphatic or aromatic hydrocarbons, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from ambient temperature to 80xc2x0 C. or to the reflux temperature of the solvent being used. The reactions are preferably conducted at ambient temperature and pressure.
The starting materials and reagents for the above described compounds are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related to, or are derived from, compounds found in nature, in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.
The compounds of the instant invention inhibit the formation of sorbitol dehydrogenase and as such have utility in the treatment of diabetic complications including but not limited to such complications as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic microangiopathy and diabetic macroangiopathy and diabetic cardiomyopathy. The utility of the compounds of the present invention as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g., humans) for example, diabetic complications such as diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic microangiopathy and diabetic macroangiopathy is demonstrated by the activity of the compounds of formula I of this invention in conventional assays. Such assays also provide a means whereby the activities of the compounds of formula I of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Male Sprague-Dawley rats (350-400 g) are used for these experiments. Diabetes is induced in some of the rats by a tail vein injection of streptozocin, 85 mg/kg. Twenty-four hours later, 4 groups of diabetic rats are given a single dose of the test compound of formula I of this invention (0.001 to 100 mg/kg) by oral gavage. Animals are sacrificed 4-6 hours after dosing and blood and sciatic nerves are harvested. Tissues and cells are extracted with 6% perchloric acid.
Sorbitol in erythrocytes and nerves is measured by a modification of the method of R. S. Clements et al. (Science, 166: 1007-8, 1969). Aliquots of tissue extracts are added to an assay system which has final concentrations of reagents of 0.033 M glycine, pH 9.4, 800 mM xcex2-nicotine adenine dinucleotide, and 4 units/ml of sorbitol dehydrogenase. After incubation for 30 minutes at room temperature, sample fluorescence is determined on a fluorescence spectrophotometer with excitation at 366 nm and emission at 452 nm. After subtracting appropriate blanks, the amount of sorbitol in each sample is determined from a linear regression of sorbitol standards processed in the same manner as the tissue extracts.
Fructose is determined by a modification of the method described by M. Ameyama, Methods in Enzymology, 89: 20-25 (1982). Resazurin is substituted for ferricyanide. Aliquots of tissue extracts are added to the assay system, which has final concentrations of reagents of 1.2 M citric acid, pH 4.5, 13 mM resazurin, 3.3 units/ml of fructose dehydrogenase and 0.068% Triton X-100. After incubation for 60 minutes at room temperature, sample fluorescence is determined on a fluorescence spectrophotometer with excitation at 560 nm and emission at 580 nm. After subtracting appropriate blanks, the amount of fructose in each sample is determined from a linear regression of fructose standards processed in the same manner as the tissue extracts.
SDH activity is measured by a modification of the method described by U. Gerlach, Methodology of Enzymaic Analyses, edited by H. U. Bergmeyer, 3, 112-117 (1983). Aliquots of sera or urine are added to the assay system, which has final concentrations of reagents of 0.1 M potassium phosphate buffer, pH 7.4, 5 mM NAD, 20 mM sorbitol, and 0.7 units/ml of sorbitol dehydrogenase. After incubation for 10 minutes at room temperature, the average change in sample absorbance is determined at 340 nm. SDH activity was presented as milliOD340 units/minute (OD340=optical density at 340 nm).
Any aldose reductase inhibitor may be used as the second compound (active agent) of this invention for combination therapies. The term aldose reductase inhibitor refers to compounds which inhibit the bioconversion of glucose to sorbitol catalyzed by the enzyme aldose reductase. Such inhibition is readily determined by those skilled in the art according to standard assays (J. Malone, Diabetes, 29:861-864, 1980. xe2x80x9cRed Cell Sorbitol, an Indicator of Diabetic Controlxe2x80x9d). A variety of aldose reductase inhibitors are described and referenced below, however, other aldose reductase inhibitors will be known to those skilled in the art. The disclosures of U.S. patents listed below are hereby incorporated by reference. Also, common chemical USAN names or other designation are in parentheses where applicable, together with reference to appropriate patent literature disclosing the compound.
The activity of an aldose reductase inhibitor in a tissue can be determined by testing the amount of aldose reductase inhibitor that is required to lower tissue sorbitol (i.e., by inhibiting the further production of sorbitol consequent to blocking aldose reductase) or lower tissue fructose (by inhibiting the production of sorbitol consequent to blocking aldose reductase and consequently the production of fructose). While not wishing to be bound by any particular theory or mechanism, it is believed that an aldose reductase inhibitor, by inhibiting aldose reductase, prevents or reduces ischemic damage as described hereinafter.
Accordingly, examples of aldose reductase inhibitors useful in the compositions and methods of this invention include:
1. 3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4-oxo-1-phthalazineacetic acid (ponalrestat, U.S. Pat. No. 4,251,528);
2. N[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl}-N-methylglycine (tolrestat, U.S. Pat. No. 4,600,724);
3. 5-[(Z,E)-xcex2-methylcinnamylidene]-4-oxo-2-thioxo-3-thiazolideneacetic acid (epalrestat, U.S. Pat. No. 4,464,382, U.S. Pat. No. 4,791,126, U.S. Pat. No. 4,831,045);
4. 3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid (zenarestat, U.S. Pat. Nos. 4,734,419, and 4,883,800);
5. 2R,4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Pat. No. 4,883,410);
6. 2R,4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Pat. No. 4,883,410);
7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid (U.S. Pat. No. 4,771,050);
8. 3,4-dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl)methyl]-2H-1,4-benzothiazine-2-acetic acid (SPR-210, U.S. Pat. No. 5,252,572);
9. N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-methyl-benzeneacetamide (ZD5522, U.S. Pat. No. 5,270,342 and U.S. Pat. No. 5,430,060);
10. (S)-6-fluorospiro[chroman-4,4xe2x80x2-imidazolidine]-2,5xe2x80x2-dione (sorbinil, U.S. Pat. No. 4,130,714);
11. d-2-methyl-6-fluoro-spiro(chroman-4xe2x80x2,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (U.S. Pat. No. 4,540,704);
12. 2-fluoro-spiro(9H-fluorene-9,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (U.S. Pat. No. 4,438,272);
13. 2,7-di-fluoro-spiro(9H-fluorene-9,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);
14. 2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);
15. 7-fluoro-spiro(5H-indenol[1,2-b]pyridine-5,3xe2x80x2-pyrrolidine)-2,5xe2x80x2-dione (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);
16. d-cis-6xe2x80x2-chloro-2xe2x80x2,3xe2x80x2-dihydro-2xe2x80x2-methyl-spiro-(imidazolidine-4,4xe2x80x2-4xe2x80x2H-pyrano(2,3-b)pyridine)-2,5-dione (U.S. Pat. No. 4,980,357);
17. spiro[imidazolidine-4,5xe2x80x2(6H)-quinoline]-2,5-dione-3xe2x80x2-chloro-7,xe2x80x28xe2x80x2-dihydro-7xe2x80x2-methyl-(5xe2x80x2-cis) (U.S. Pat. No. 5,066,659);
18. (2S,4S)-6-fluoro-2xe2x80x2,5xe2x80x2-dioxospiro(chroman-4,4xe2x80x2-imidazolidine)-2-carboxamide (U.S. Pat. No. 5,447,946); and
19. 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H),3xe2x80x2-pyrrolidine]-1,2xe2x80x2,3,5xe2x80x2(2H)-tetrone (ARI-509, U.S. Pat. No. 5,037,831).
Other aldose reductase inhibitors include compounds having formula ARI, 
xe2x80x83or a pharmaceutically acceptable salt thereof, wherein
Z in the compound of formula ARI is O or S;
R1 in the compound of formula ARI is hydroxy or a group capable of being removed in vivo to produce a compound of formula ARI wherein R1 is OH; and
X and Y in the compound of formula ARI are the same or different and are selected from hydrogen, trifluoromethyl, fluoro, and chloro.
A preferred subgroup within the above group of aldose reductase inhibitors includes numbered compounds 1, 2, 3, 4, 5, 6, 9, 10, and 17, and the following compounds of Formula ARI:
20. 3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl)-4-oxophthalazin-1-yl-acetic acid [R1=hydroxy; X=F; Y=H];
21. 3-(5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; Xxe2x95x90Y=F];
22. 3-(5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; X=Cl; Y=H];
23. 3-(5,7-dichlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; Xxe2x95x90Y=Cl];
24. 3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-ylmethyl)phthalazin-1-ylacetic acid [R1=hydroxy; X=CF3; Y=H];
25. 3,4-dihydro-3-(5-fluorobenzoxazol-2-ylmethyl)-4-oxophthalazin-1-yl-acetic acid [R1=hydroxy; X=F; Y=H];
26. 3-(5,7-difluorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; Xxe2x95x90Y=F];
27. 3-(5-chlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; X=Cl; Y=H];
28. 3-(5,7-dichlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; Xxe2x95x90Y=Cl]; and
29. zopolrestat; 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-[R1=hydroxy; X=trifluoromethyl; Y=H].
In compounds 20-23, and 29 Z is S. In compounds 24-28, Z is O.
Of the above subgroup, compounds 20-29 are more preferred with 29 especially preferred.
An especially preferred aldose reductase inhibitor is 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-.
The term xe2x80x9cacyl radical of a carboxylic acid aldose reductase inhibitorxe2x80x9d refers to any of the above-mentioned aldose reductase inhibitors which contains a carboxylic acid group in which the carboxylic acid group is replaced with a carbonyl radical.
The aldose reductase inhibitor compounds of this invention are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis, particularly in view of the pertinent patent specification descriptions.
An amount of the aldose reductase inhibitor of this invention that is effective for the activities of this invention may be used. Typically, an effective dosage for the aldose reductase inhibitors of this invention is in the range of about 0.1 mg/kg/day to 100 mg/kg/day in single or divided doses, preferably 0.1 mg/kg/day to 20 mg/kg/day in single or divided doses.
Any sodium hydrogen ion exchange (NHE-1) inhibitor may be used as the second compound (active agent) of this invention for combination therapies. The term NHE-1 inhibitor refers to compounds which inhibit the sodium/proton (Na+/H+)exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused or aggravated by the acceleration of the sodium/proton (N+/H+) exchange transport system, for example, cardiovascular diseases [e.g., arteriosclerosis, hypertension, arrhythmia (e.g. ischemic arrhythmia, arrhythmia due to myocardial infarction, myocardial stunning, myocardial dysfunction, arrhythmia after PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic shock, endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus, diabetic nephropathy, ischemic acute renal failure, etc.) organ disorders associated with ischemia or ischemic reperfusion [e.g. heart muscle ischemic reperfusion associated disorders, acute renal failure, or disorders induced by surgical treatment such as coronary artery bypass grafting (CABG) surgeries, vascular surgeries, organ transplantation, non-cardiac surgeries or percutaneous transluminal coronary angioplasty (PTCA)], cerebrovascular diseases (e.g. ischemic stroke, hemorrhagic stroke, etc.), cerebro ischemic disorders (e.g. disorders associated with cerebral infarction, disorders caused after cerebral apoplexy as sequelae, or cerebral edema. NHE-1 inhibitors can also be used as an agent for myocardial protection during coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), PTCI, organ transplantation, or non-cardiac surgeries. The utility of NHE-1 inhibitors as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g. humans) for example, myocardial protection during surgery or mycardial protection in patients presenting with ongoing cardiac or cerebral ischemic events or chronic cardioprotection in patients with diagnosed coronary heart disease, or at risk for coronary heart disease, cardiac dysfunction or myocardial stunning is demonstrated by the activity of the compounds of formula I of this invention in conventional preclinical cardioprotection assays [see the in vivo assay in Klein, H. et al., Circulation 92:912-917 (1995); the isolated heart assay in Scholz, W. et al., Cardiovascular Research 29:260-268 (1995); the antiarrhythmic assay in Yasutake M. et al., Am. J. Physiol., 36: H2430-H2440 (1994); the NMR assay in Kolke et al., J. Thorac. Cardiovasc. Surg. 112: 765-775 (1996)] and the additional in vitro and in vivo assays described below. Such assays also provide a means whereby the activities of the compounds of formula I of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
NHE-1 inhibitors are disclosed in U.S. Pat. No. 5,698,581, European Patent Application Publication No. EP 803 501 A1, International Patent Application Publication Nos. WO 94/26709 and PCT/JP97/04650, each of which is incorporated herein by reference. The NHE-1 inhibitors disclosed therein have utility in the combination of this invention. Said NHE-1 inhibitors can be prepared as disclosed therein.
Preferred NHE-1 inhibitors include compounds of the formula NHE, 
a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug, wherein
Z in the compound of formula NHE is carbon connected and is a five-membered, diaza, diunsaturated ring having two contiguous nitrogens, said ring optionally mono-, di-, or tri-substituted with up to three substituents independently selected from R1, R2 and R3; or
Z in the compound of formula NHE carbon connected and is a five-membered, triaza, diunsaturated ring, said ring optionally mono- or di-substituted with up to two substituents independently selected from R4 and R5;
wherein R1, R2, R3, R4 and R5 in the compound of formula NHE are each independently hydrogen, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkylthio, (C3-C4)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, M or M(C1-C4)alkyl, any of said previous (C1-C4)alkyl moieties optionally having from one to nine fluorines; said (C1-C4)alkyl or (C3-C4)cycloalkyl optionally mono-or di-substituted independently with hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl or mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl; and said (C3-C4)cycloalkyl optionally having from one to seven fluorines;
wherein M in the compound of formula NHE is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said M in the compound of formula NHE is optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated, or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen optionally substituted with (C1-C4)alkyl and additionally R6, R7 and R8 are optionally hydroxy, nitro, halo, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl, formyl, (C1-C4)alkanoyl, (C1-C4)alkanoyloxy, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C5-C7)cycloalkenyl,
wherein said (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C7)alkanoyl, (C1-C4)alkylthio, mono-N- or di-N,N-(C1-C4)alkylamino or (C3-C7)cycloalkyl R6, R7 and R8 substituents are optionally mono-substituted independently with hydroxy, (C1-C4)alkoxycarbonyl, (C3-C7)cycloalkyl, (C1-C4)alkanoyl, (C1-C4)alkanoylamino, (C1-C4)alkanoyloxy, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, nitro, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl or optionally substituted with one to nine fluorines.
Especially preferred NHE-1 inhibitors include [1-(8-bromoquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(6-chloroquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(indazol-7-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(benzimidazol-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(1-isoquinolyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine; [1-(indazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(indazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(benzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(1-methylbenzimidazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; 1-(5-quinolinyl)-5-n-propyl-1H-pyrazole-4-carbonyl]guanidine; [1-(5-quinolinyl)-5-isopropyl-1H-pyrazole-4-carbonyl]guanidine; [5-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; [1-(2-methylbenzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(1,4-benzodioxan-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(benzotriazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(3-chloroindazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(5-quinolinyl)-5-butyl-1H-pyrazole-4-carbonyl]guanidine; [5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; [5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-4-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-methoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-4-methylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2,5-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2,3-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-aminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-fluoro-6-trifluoromethylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-dimethylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-trifluoromethyl-4-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidine; [5-methyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine; [5-ethyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]guanidine or or a pharmaceutically acceptable salt thereof.
The preferred and especially preferred NHE-1 inhibitors disclosed in the above two paragraphs can be prepared according to methods set forth in International Patent Application No. PCT/IB99/00206 or as set forth below, where the variables in the following schemes and description refer only to the NHE-1 compounds. 
According to Scheme I, the Formula I-a compound, wherein R4 is as described above for the compound of formula NHE, is dissolved or suspended in an aqueous alkali metal hydroxide solution (e.g. 1 N sodium hydroxide) along with sodium nitrite and the mixture is added to an aqueous acidic solution (e.g. 10% v/v sulfuric acid) at a pH of about 0 at a temperature of about 0xc2x0 C. to about 5xc2x0 C. for about 30 min to about 1 hour. The resulting mixture is filtered to yield the Formula I-b oxime. Alternatively, the Formula I-a compound is dissolved in 1:1 acetic acid/propionic acid and solid sodium nitrite is added at about 0xc2x0 C. The reaction mixture is stirred at about 0xc2x0 C. for about 2 hours, then poured into ice water and the Formula I-b oxime is obtained by filtration.
The Formula I-b compound is reacted with a Formula I-c compound, wherein R5 is as described above for the compound of formula NHE in a protic solvent such as ethanol at a temperature of about 50xc2x0 C. to about 110xc2x0 C. for about 10 min to about 1 hour to form the Formula I-d hydrazone.
The Formula I-d hydrazone is cyclized and hydrolyzed to the Formula I-e triazole in an alcoholic solvent such as 2-ethoxyethanol under basic conditions (e.g., potassium hydroxide) at a temperature of about 100xc2x0 C. to about 175xc2x0 C. for about xc2xd hour to about 2 hours followed by acidification to yield the Formula I-e triazole acid.
The Formula I-e acid is coupled with guanidine in the presence of a suitable coupling agent. A suitable coupling agent is one which transforms a carboxylic acid into a reactive species which forms an amide linkage on reaction with an amine.
The coupling agent may be a reagent which effects this condensation in a one pot process when mixed together with the carboxylic acid and guanidine. Exemplary coupling reagents are 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-hydroxybenzotriazole (EDC/HBT), dicyclohexylcarbodiimide/hydroxybenzotriazole(HBT), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and diethylphosphorylcyanide. The coupling is performed in an inert solvent, preferably an aprotic solvent at a temperature of about xe2x88x9220xc2x0 C. to about 50xc2x0 C. for about 1 to about 48 hours, in the presence of excess guanidine as base. Exemplary solvents include acetonitrile, dichloromethane, dimethylformamide and chloroform or mixtures thereof.
The coupling agent may also be that agent which converts the carboxylic acid to an activated intermediate which is isolated and/or formed in a first step and allowed to react with guanidine in a second step. Examples of such coupling agents and activated intermediates are thionyl chloride or oxalyl chloride to form the acid chloride, cyanuric fluoride to form an acid fluoride or an alkyl chloroformate such as isobutyl or isopropenyl chloroformate or propanephosphonic anhydride (propanephosphonic acid anhydride, PPA) (with a tertiary amine base) to form a mixed anhydride of the carboxylic acid, or carbonyldiimidazole to form an acylimidazole. If the coupling agent is oxalyl chloride, it is advantageous to employ a small amount of dimethylformamide as cosolvent with another solvent (such as dichloromethane) to catalyze the formation of the acid chloride. This activated acid derivative may be coupled by mixing with excess guanidine in an appropriate solvent together with an appropriate base. Appropriate solvent/base combinations are for example, dichloromethane, dimethylformamide or acetonitrile or mixtures thereof in the presence of excess guanidine as base. Other appropriate solvent/base combinations include water or a (C1-C5)alcohol or a mixture thereof together with a cosolvent such as dichloromethane, tetrahydrofuran or dioxane and a base such as sodium, potassium or lithium hydroxide in sufficient quantity to consume the acid liberated in the reaction. Use of these coupling agents and appropriate selection of solvents and temperatures are known to those skilled in the art or can be readily determined from the literature. These and other exemplary conditions useful for coupling carboxylic acids are described in Houben-Weyl, Vol XV, part II, E. Wunsch, Ed., G. Theime Verlag, 1974, Stuttgart; M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag, Berlin 1984; and The Peptides, Analysis, Synthesis and Biology (ed. E. Gross and J. Meienhofer), vols 1-5 (Academic Press, NY 1979-1983).
According to Scheme II, the Formula II-a primary amine wherein R5 is as described above for the compound of formula NHE is reacted with a Formula II-b xcex1diazo-xcex2-keto-ester wherein R4 is as described above for the compound of formula NHE, and R is lower alkyl, in the presence of titanium tetrachloride analogously to the method described in Eguchi S. et al. Synthesis 1993, 793 to form the Formula II-c triazole carboxylic acid ester. The Formula II-c ester is converted directly to the acylguanidine II-d by reaction with guanidine in an alcoholic solvent at a temperature of about 60 to about 110xc2x0 C., preferably refluxing methanol, for a period of 8 to 20 hours.
According to Scheme III, the Formula III-a compound wherein R4 and R5 are as described above for the compound of formula NHE is treated with Lawesson""s reagent (i.e., 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) in an aprotic solvent such as dimethoxyethane at a temperature of about 20xc2x0 C. to about 120xc2x0 C. for about one to eight hours. The resulting thioamide is treated with an alkylating agent such as methyl iodide in a polar, inert solvent such as acetone, conveniently at ambient temperature for about eight hours to about forty-eight hours. The resulting compound is reacted with anhydrous hydrazine in an alcoholic solvent at a temperature of about 0xc2x0 C. to about 25xc2x0 C. for about one to eight hours to provide the Formula III-b compound (analogously as described in Doyle and Kurzer, Synthesis 1974, 583).
The Formula III-b compound is treated with a monoalkyloxalyl chloride in an aprotic solvent at a temperature of about 25xc2x0 C. to about 50xc2x0 C. for about one to eight hours to provide the Formula III-c carboxylic ester compound wherein R is lower alkyl. The Formula III-c ester is directly coupled with guanidine in an alcoholic solvent at a temperature of about 60xc2x0 C. to about 110xc2x0 C., preferably refluxing methanol, for a period of eight to twenty hours, to prepare the Formula III-d triazole carbonyl guanidines.
According to Scheme IV the Formula IV-a compound wherein R5 is as described above for the compound of formula NHE is treated with methyl iodide in an inert solvent, conveniently at ambient temperature for about four to twenty-four hours. The resulting compound is reacted with anhydrous R4-hydrazine (wherein R4 is as described above for the compound of formula NHE) in an alcoholic solvent at a temperature of about 0xc2x0 C. to about 25xc2x0 C. for about one to eight hours to provide the Formula IV-b amidrazone compound (analogously as described in Doyle and Kurzer, Synthesis 1974, 583).
The Formula IV-b compound is treated with a monoalkyloxalyl chloride in an aprotic solvent at a temperature of about 25xc2x0 C. to about 50xc2x0 C. for about one to eight hours to provide the Formula IV-c carboxylic ester compound wherein R is lower alkyl. The Formula IV-c ester is directly coupled with guanidine in an alcoholic solvent at a temperature of about 60xc2x0 C. to about 110xc2x0 C., preferably refluxing methanol, for a period of eight to twenty hours to prepare the Formula IV-d triazole carbonyl guanidines.
According to Scheme V the Formula V-a compound wherein R1 is as described above for the compound of formula NHE is combined with excess (CH3O)2C(R3)N(CH3)2 (N,N-dimethyl amide dimethyl acetal) wherein R3 is as described above for the compound of formula NHE, optionally in the presence of an acid catalyst such as p-toluenesulfonic acid at a temperature of about 90xc2x0 C. to about 110xc2x0 C. for about one to about two hours to prepare the Formula V-c compound above.
The Formula V-c compound is cyclized with a Formula V-d compound, wherein R2 is as described above for the compound of formula NHE, in an inert solvent such as ethanol at a temperature of about 20xc2x0 C. to about 30xc2x0 C. for about 5 minutes to about one hour followed by heating to a temperature of about 70xc2x0 C. to about 110xc2x0 C. for about two hours to about four hours to form the Formula V-f pyrazole.
Alternatively, according to Scheme V the Formula V-a compound, wherein R1 is as described above for the compound of formula NHE, is combined with a triethylorthoester (i.e., R3C(OEt)3 wherein R3 is as described above for the compound of formula NHE) and acetic anhydride at a temperature of about 120xc2x0 C. to about 150xc2x0 C. for about two to about five hours to prepare the Formula V-b compound.
The Formula V-b compound is cyclized with a Formula V-d compound, wherein R2 is as described above for the compound of formula NHE, to form the Formula V-c pyrazole.
The Formula V-c pyrazole is hydrolyzed with a base such as sodium hydroxide or lithium hydroxide in a solvent such as water and/or methanol and/or THF conveniently at ambient temperature or at elevated temperature (e.g., reflux) for about one hour to about five hours to prepare the Formula V-f acid.
The Formula V-f acid is coupled with guanidine in the presence of a suitable coupling agent as described for the above coupling of the Formula I-e acid and guanidine. In one embodiment, the Formula V-f acid is activated with thionyl chloride at a temperature of about 60xc2x0 C. to about 90xc2x0 C. for about fifteen minutes to about two hours. The resulting activated acid chloride is combined with guanidine hydrochloride and an inorganic base (e.g., sodium hydroxide) in anhydrous tetrahydrofuran and optionally methanol and/or water. The solution is heated, conveniently at reflux, for about one hour to about eight hours to prepare the Formula V-g compound.
Alternatively according to Scheme V the Formula V-e compound can be directly converted to the Formula V-g compound by several methods. For example, the Formula V-e compound can be heated in the presence of excess guanidine, in a polar protic solvent for example, methanol or isopropanol at a suitable temperature conveniently, at reflux for about one to about seventy-two hours. This transformation may also be performed by repeatedly removing the solvent, for example removing ethanol or toluene about four times, from a mixture of the Formula V-e compound and excess guanidine at a pressure of about one to about 100 mmHg and at a temperature of about 25xc2x0 C. to about 95xc2x0 C. This reaction may also be performed in the absence of solvent by heating the mixture of the Formula V-e compound and excess guanidine at a temperature of about 100xc2x0 C. to about 180xc2x0 C., optionally at about a pressure of about 1 to about 100 mmHg for about five minutes to about eight hours.
According to Scheme VI, the Formula VI-a compound, wherein R3 is as described above for the compound of formula NHE, is reacted with the Formula VI-b compound, wherein R1 and R2 are as described above for the compound of formula NHE, in an aprotic solvent at a temperature of about 0xc2x0 C. to about 25xc2x0 C. for about two hours to about twenty-four hours in the presence of an appropriate amine base, such as triethylamine, to form the Formula VI-c compound.
The resulting Formula VI-c compound is hydrolyzed and coupled with guanidine using one of the methods described in earlier Schemes, such as the method employing carbonyldiimidazole, to form the Formula VI-d compound.
According to Scheme VII, the Formula VII-a hydrazine, wherein R2 is as described above for the compound of formula NHE, is reacted with the appropriate Formula VII-b compound to form the Formula VII-c pyrazole ester wherein R is lower alkyl according to the method of Bajnati, A. and Hubert-Habart, M. Bull. Soc. Chim. France 1988, 540. The resulting pyrazole ester is converted to the Formula VIII-d acyl guanidine using the hydrolysis and coupling methods described above.
According to Scheme VIII, the Formula VIII-a compound wherein R2 and R1 are as described above for the compound of formula NHE is transformed to the Formula VIII-b lithium salt where R is lower alkyl according to the method described in J. Het. Chem. 1989, 26, 1389. The Formula VIII-b lithium salt is combined with the Formula VIII-c hydrazine, wherein R3 is as described above for the compound of formula NHE, in an inert solvent such as ethanol, in the presence of a mineral acid, at a temperature of about 20xc2x0 C. to about 30xc2x0 C. for about five minutes to about one hour followed by heating to a temperature of about 70xc2x0 C. to about 110xc2x0 C. for two hours to about four hours to form both the Formula VIII-d and VIII-e pyrazoles. The Formula VIII-d and VIII-e pyrazoles are converted to the Formula VIII-f and VIII-g acyl guanidines respectively using the hydrolysis and coupling methods described above. Some of the methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in Formula I precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
The compounds of formula I of the present invention, when used in combination with NHE-1 inhibitors, inhibit the sodium/proton (Na+/H+) exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused or aggravated by the acceleration of the sodium/proton (Na+/H+) exchange transport system, for example, cardiovascular diseases [e.g., arteriosclerosis, hypertension, arrhythmia (e.g. ischemic arrhythmia, arrhythmia due to myocardial infarction, myocardial stunning, myocardial dysfunction, arrhythmia after PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic shock, endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus, diabetic nephropathy, ischemic acute renal failure, etc.) organ disorders associated with ischemia or ischemic reperfusion [e.g. heart muscle ischemic reperfusion associated disorders, acute renal failure, or disorders induced by surgical treatment such as coronary artery bypass grafting (CABG) surgeries, vascular surgeries, organ transplantation, non-cardiac surgeries or percutaneous transluminal coronary angioplasty (PTCA)], cerebrovascular diseases (e.g. ischemic stroke, hemorrhagic stroke, etc.), cerebro ischemic disorders (e.g. disorders associated with cerebral infarction, disorders caused after cerebral apoplexy as sequelae, or cerebral edema.
Preferably, the compounds of formula I of this invention can be used in combination with NHE-1 inhibitors as agents for myocardial protection before, during, or after coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), organ transplantation, or non-cardiac surgeries.
Preferably, the compounds of formula I of this invention can be used in combination with NHE-1 inhibitors as agents for myocardial protection in patients presenting with ongoing cardiac (acute coronary syndromes, e.g. myocardial infarction or unstable angina) or cerebral ischemic events (e.g. stroke).
Preferably, the compounds of formula I of this invention can be used in combination with NHE-1 inhibitors as agents for chronic myocardial protection in patients with diagnosed coronary heart disease (e.g. previous myocardial infarction or unstable angina) or patients who are at high risk for myocardial infarction (age greater than 65 and two or more risk factors for coronary heart disease).
In addition, a combination of the compounds of formula I of this invention with NHE-1 inhibitors has a strong inhibitory effect on the proliferation of cells, for example the proliferation of fibroblast cells and the proliferation of the smooth muscle cells of the blood vessels. For this reason, the combination of the compounds of formula I of this invention with NHE-1 inhibitors of this invention is a valuable therapeutic agent for use in diseases in which cell proliferation represents a primary or secondary cause and may, therefore, be used as antiatherosclerotic agents, and as agents against diabetic late complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, glomerular nephrosclerosis, organ hypertrophies or hyperplasias, in particular hyperplasia or hypertrophy of the prostate, pulmonary fibrosis, diabetic complications or recurrent stricture after PTCA, or diseases caused by endothelial cell injury.
The utility of the combination of compounds of the present invention with NHE-1 inhibitors as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g. humans) for example, myocardial protection during surgery or mycardial protection in patients presenting with ongoing cardiac or cerebral ischemic events or chronic cardioprotection in patients with diagnosed coronary heart disease, or at risk for coronary heart disease, cardiac dysfunction or myocardial stunning is demonstrated by the activity of said combination in conventional preclinical cardioprotection assays [see the in vivo assay in Klein, H. et al., Circulation 92:912-917 (1995); the isolated heart assay in Scholz, W. et al., Cardiovascular Research 29:260-268 (1995); the antiarrhythmic assay in Yasutake M. et al., Am. J. Physiol., 36:H2430-H2440 (1994); the NMR assay in Kolke et al., J. Thorac. Cardiovasc. Surg. 112: 765-775 (1996)] and the additional in vitro and in vivo assays described below. Such assays also provide a means whereby the activities of the compounds of formula I of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Methodologies for measurement of human NHE-1 activity and inhibitor potency are based on those published by Watson et al., Am. J. Physiol., 24:G229--G238, 1991), where NHE-mediated recovery of intracellular pH is measured following intracellular acidification. Thus, fibroblasts stably expressing human NHE-1 (Counillon, L. et al., Mol. Pharmacol., 44:1041-1045 (1993) are plated onto collagen coated 96 well plates (50,000/well) and grown to confluence in growth media (DMEM high glucose, 10% fetal bovine serum, 50 u/ml penicillin and streptomycin). Confluent plates are incubated for 30 minutes at 37xc2x0 C. with the pH sensitive fluorescent probe BCECF (5 xcexcM; Molecular Probes, Eugene, Oreg.). BCECF loaded cells are incubated for 30 minutes at 37xc2x0 C. in acid loading media (70 mM choline chloride, 50 mM NHCl4, 5 mM KCl, 1 mM MgCl2, 1.8 mM CaCl2, 5 mM glucose, 10 mM HEPES, pH 7.5), and then placed in a Fluorescent Imaging Plate Reader (Molecular Devices, CA). BCECF fluorescence is monitored using excitation and emission wavelengths of 485 nM and 525 nM, respectively. Intracellular acidification is initiated via rapid replacement of acid loading media with recovery media (120 mM NaCl, 5 mM KCl, 1 mM MgCl2, 1.8 mM CaCl2, 5 mM glucose, 10 mM HEPES, pH 7.5)xc2x1test combination, and NHE-mediated recovery of intracellular pH is monitored as the subsequent time-dependent increase BCECF fluorescence. The potency of the combinations of the compounds of formula I of this invention with NHE-1 inhibitors is calculated as the concentration that reduces recovery of intracellular pH by 50% (IC50). Under these conditions reference NHE inhibitors amiloride and HOE-642 had IC50 values for human NHE-1 of 50 xcexcM and 0.5 xcexcM, respectively.
As background information, it is noted that brief periods of myocardial ischemia followed by coronary artery reperfusion protects the heart from subsequent severe myocardial ischemia (Murry et al., Circulation 74:1124-1136, 1986).
The therapeutic effects of the combination of the compounds of formula I of this invention with NHE-1 inhibitors in preventing heart tissue damage resulting from an ischemic insult can be demonstrated in vitro along lines presented in Liu et al. (Cardiovasc. Res., 28:1057-1061, 1994), as described specifically herein. Cardioprotection, as indicated by a reduction in infarcted myocardium, can be induced pharmacologically using adenosine receptor agonists in isolated, retrogradely perfused rabbit hearts as an in vitro model of myocardial ischemic preconditioning (Liu et al., Cardiovasc. Res., 28:1057-1061, 1994). The in vitro test described below demonstrates that a test compound or, in this case a test combination (i.e., a combination of a compound of formula I with an NHE-1 antagonist) can also pharmacologically induce cardioprotection, i.e., reduced myocardial infarct size, when administered to a rabbit isolated heart. The effects of the test combination are compared to ischemic preconditioning and the A1/A3 adenosine agonist, APNEA (N6-[2-(4-aminophenyl)ethyl]adenosine), that has been shown to pharmacologically induce cardioprotection in the rabbit isolated heart (Liu et al., Cardiovasc. Res., 28:1057-1061, 1994). The exact methodology is described below.
The protocol used for these experiments closely follows that described by Liu et al., Cardiovasc. Res., 28:1057-1061, 1994. Male New Zealand White rabbits (3-4 kg) are anesthetized with sodium pentobarbital (30 mg/kg, i.v.). After deep anesthesia is achieved (determined by the absence of an ocular blink reflex) the animal is intubated and ventilated with 100% O2 using a positive pressure ventilator. A left thoracotomy is performed, the heart exposed, and a snare (2-0 silk) is placed loosely around a prominent branch of the left coronary artery, approximately ⅔ the distance towards the apex of the heart. The heart is removed from the chest and rapidly ( less than 30 sec) mounted on a Langendorff apparatus. The heart is retrogradely perfused in a non-recirculating manner with a modified Krebs solution (NaCl 118.5 mM, KCl 4.7 mM, MgSO4 1.2 mM, KH2PO4 1.2 mM, NaHCO3 24.8 mM, CaCl2 2.5 mM, and glucose 10 mM), at a constant pressure of 80 mmHg and a temperature of 37xc2x0 C. Perfusate pH is maintained at 7.4-7.5 by bubbling with 95% O2/5% CO2. Heart temperature is tightly controlled by using heated reservoirs for the physiological solution and water jacketing around both the perfusion tubing and the isolated heart. Heart rate and left ventricular pressures are determined via a latex balloon which is inserted in the left ventricle and connected by stainless steel tubing to a pressure transducer. The intraventricular balloon is inflated to provide a systolic pressure of 80-100 mmHg, and a diastolic pressurexe2x89xa610 mmHg. Total coronary flow is also continuously monitored using an in-line flow probe and normalized for heart weight.
The heart is allowed to equilibrate for 30 minutes, over which time the heart must show stable left ventricular pressures within the parameters outlined above. If the heart rate falls below 180 bpm at any time prior to the 30 minutes period of regional ischemia, the heart is paced at about 200 bpm for the remainder of the experiment lschemic preconditioning is induced by total cessation of cardiac perfusion (global ischemia) for 5 minutes, followed by reperfusion for 10 minutes. The regional ischemia is provided by tightening the snare around the coronary artery branch. Following the 30 minutes regional ischemia, the snare is released and the heart reperfused for an additional 120 minutes.
Pharmacological cardioprotection is induced by infusing the test combination, i.e., a combination of a compound of formula I with an NHE-1 inhibitor, at predetermined concentrations, starting 30 minutes prior to the 30 minutes regional ischemia, and continuing until the end of the 120 minutes reperfusion period. Hearts which receive the test combination do not undergo the period of ischemic preconditioning. The reference compound, APNEA (500 nM) is perfused through hearts (which do not receive the test compound) for a 5 minutes period which ends 10 minutes before the 30 minutes regional ischemia.
At the end of the 120 minutes reperfusion period, the coronary artery snare is tightened, and a 0.5% suspension of fluorescent zinc cadmium sulfate particles (1-10 xcexcM) Duke Scientific Corp. (Palo Alto, Calif.) is perfused through the heart; this stains all of the myocardium, except that area-at-risk for infarct development (area-at-risk). The heart is removed from the Langendorff apparatus, blotted dry, wrapped in aluminum foil and stored overnight at xe2x88x9220xc2x0 C. The next day, the heart is sliced into 2 mm transverse sections from the apex to the top of the ventricles. The slices are stained with 1% triphenyl tetrazolium chloride (TTC) in phosphate-buffered saline for 20 minutes at 37xc2x0 C. Since TTC reacts with living tissue (containing NAD-dependent dehydrogenases), this stain differentiates between living (red stained) tissue, and dead tissue (unstained infarcted tissue). The infarcted area (no stain) and the area-at-risk (no fluorescent particles) are calculated for each slice of left ventricle using a precalibrated image analyzer. To normalize the ischemic injury for differences in the area-at-risk between hearts, the data is expressed as the ratio of infarct area vs. area-at-risk (% IA/AAR). All data are expressed as meanxc2x1SE and compared statistically using a Mann-Whitney non-parametric test with a Bonferroni correction for multiple comparisons. Significance is considered as p less than 0.05.
The results from the above in vitro test demonstrate that a combination of a compound of this invention with an NHE-1 inhibitor induce significant cardioprotection relative to the control group.
The therapeutic effects of a combination of a compound of formula I of this invention with an NHE-1 inhibitor in preventing heart tissue damage otherwise resulting from an ischemic insult can also be demonstrated in vivo along lines presented in Liu et al. (Circulation, Vol. 84:350-356, 1991) as described specifically herein. The in vivo assay tests the cardioprotection of the test combination, i.e., a compound of formula I together with an NHE-1 inhibitor, relative to the control group which receives saline vehicle. Cardioprotection, as indicated by a reduction in infarcted myocardium, can be induced pharmacologically using intravenously administered adenosine receptor agonists in intact, anesthetized rabbits studied as an in situ model of myocardial ischemic preconditioning (Liu et al., Circulation 84:350-356, 1991). The in vivo assay tests whether the instant combination of a compound of formula I with an NHE-1 inhibitor can pharmacologically induce cardioprotection, i.e., reduced myocardial infarct size, when parenterally administered to intact, anesthetized rabbits. The effects of the combination of a compound of formula I of this invention with an NHE-11 inhibitor can be compared to ischemic preconditioning using the A1 adenosine agonist, N6-1-(phenyl-2R-isopropyl) adenosine (PIA) that has been shown to pharmacologically induce cardioprotection in intact anesthetized rabbits studied in situ (Liu et al., Circulation 84:350-356, 1991). The methodology is described below.
Surgery: New Zealand White male rabbits (3-4 kg) are anesthetized with sodium pentobarbital (30 mg/kg, i.v.). A tracheotomy is performed via a ventral midline cervical incision and the rabbits are ventilated with 100% oxygen using a positive pressure ventilator. Catheters are placed in the left jugular vein for drug administration and in the left carotid artery for blood pressure measurements. The hearts are then exposed through a left thoracotomy and a snare (00 silk) placed around a prominent branch of the left coronary artery. Ischemia is induced by pulling the snare tight and clamping it in place. Releasing the snare allows the affected area to reperfuse. Myocardial ischemia is evidenced by regional cyanosis; reperfusion is evidenced by reactive hyperemia.
Protocol: Once arterial pressure and heart rate have been stable for at least 30 minutes the test is started. Ischemic preconditioning is induced by occluding the coronary artery for 5 minutes followed by a 10 minutes reperfusion. Pharmacological preconditioning is induced by infusing the test combination, i.e., a combination of a compound of formula I of this invention with an NHE-1 inhibitor, over, for example, 5 minutes and allowing 10 minutes before further intervention or by infusing the adenosine agonist, PIA (0.25 mg/kg). Following ischemic preconditioning, pharmacological preconditioning or no conditioning (unconditioned, vehicle control) the artery is occluded for 30 minutes and then reperfused for two hours to induce myocardial infarction. The test combination and PIA are dissolved in saline or other suitable vehicle and delivered at 1 to 5 mg/kg, respectively.
Staining (Liu et al., Circulation 84:350-356, 1991): At the end of the 2 hour reperfusion period, the hearts are quickly removed, hung on a Langendorff apparatus, and flushed for 1 minute with normal saline heated to body temperature (38xc2x0 C.). The silk suture used as the snare is then tied tightly to reocclude the artery and a 0.5% suspension of fluorescent zinc cadmium sulphate particles (1-10 xcexcm) Duke Scientific Corp. (Palo Alto, Calif.) is infused with the perfusate to stain all of the myocardium except the area at risk (nonfluorescent ventricle). The hearts are then quickly frozen and stored overnight at xe2x88x9220xc2x0 C. On the following day, the hearts are cut into 2 mm slices and stained with 1% triphenyl tetrazolium chloride (TTC). Since TTC reacts with living tissue, this stain differentiates between living (red stained) tissue, and dead tissue (unstained infarcted tissue). The infarcted area (no stain) and the area at risk (no fluorescent particles) are calculated for each slice of left ventricle using a pre-calibrated image analyzer. To normalize the ischemic injury for differences in the area at risk between hearts, the data is expressed as the ratio of infarct area vs. area at risk (% IA/AAR). All data are expressed as Meanxc2x1SEM and compared statistically using single factor ANOVA or Mann Whitney non parametric test. Significance is considered as p less than 0.05.
The combination of a compound of formula I of this invention with an NHE-1 inhibitor can be tested for their utility in reducing or preventing ischemic injury in non-cardiac tissues, for example, the brain, or the liver, utilizing procedures reported in the scientific literature. The combination of a compound of formula I of this invention with an NHE-1 inhibitor in such tests can be administered by the preferred route and vehicle of administration and at the preferred time of administration either prior to the ischemic episode, during the ischemic episode, following the ischemic episode (reperfusion period) or during any of the below-mentioned experimental stages.
The benefit of the combination of NHE-1 inhibitors and compounds of formula I of this invention to reduce ischemic brain damage can be demonstrated, for example, in mammals using the method of Park, et al (Ann. Neurol. 1988;24:543-551). According to the procedure of Park, et al., adult male Sprague Dawley rats are anesthetized initially with 2% halothane, and thereafter by mechanical ventilation with a nitrous oxide-oxygen mixture (70%:30%) containing 0.5-1% halothane. A tracheostomy is then performed. The stroke volume of the ventilator is adjusted to maintain arterial carbon dioxide tension at approximately 35 mm Hg and adequate arterial oxygenation (PaO2 greater than 90 mm Hg). Body temperature can be monitored by a rectal thermometer, and the animals can be maintained normothermic, if necessary, by external heating. The animals next undergo subtemporal craniectomy to expose the main trunk of the left middle cerebral artery (MCA) under an operating microscope, and the exposed artery is occluded with microbipolar coagulation to generate large ischemic lesions in the cerebral cortex and basal ganglia. After three hours of MCA occlusion, the rats are deeply anesthetized with 2% halothane and a thoracotomy is performed to infuse heparinized saline into the left ventricle. The effluent is collected via an incision of the right atrium. The saline washout is followed by approximately 200 ml of a 40% formaldehyde, glacial acetic acid and absolute methanol solution (FAM; 1:1:8, v/v/v), then the animals are decapitated and the head is stored in fixative for 24 hours. The brain is then removed, dissected, embedded in paraffin wax, and sectioned (approximately 100 sections 0.2mm per brain). The sections are then stained with hematoxylin-eosin or with a combination of cresyl violet and Luxol fast blue, and examined by light microscopy to identify and quantitate the ischemic damage using a precalibrated image analyzer. The ischemic volumes and areas are expressed in absolute units (mm3 and mm2) and as a percentage of the total region examined. The effect of the compositions and methods of this invention to reduce ischemic brain damage induced by MCA occlusion is noted based on a reduction in the area or volume of relative or absolute ischemic damage in the brain sections from the rats in the treatment group compared to brain sections from rats in a placebo-treated control group.
Other methods which could alternatively be utilized to demonstrate the benefit of the invention to reduce ischemic brain damage include those described by Nakayama, et al. in Neurology 1988, 38:1667-1673; Memezawa, et al. in Stroke 1992, 23:552-559; Folbergrova, et al. in Proc. Natl. Acad. Sci 1995, 92:5057-5059; and Gotti, et al. in Brain Res. 1990, 522.290-307.
The benefit of the compositions and methods of this invention to reduce ischemic liver damage can be demonstrated, for example, in mammals using the method of Yokoyama, et al. (Am. J. Physiol. 1990;258:G564-G570). According to the procedure of Yokoyama, et al., fasted adult male Sprague Dawley rats are anesthetized with sodium pentobarbital (40 mg/kg i.p.), then the animals are tracheotomized and mechanically ventilated with room air. The liver is extirpated and placed in an environmental chamber maintained at constant temperature (37xc2x0 C.), then perfused through the portal vein at a constant pressure of 15 cm H2O with a modified, hemoglobin-free Krebs-Henseleit buffer (in mM: 118 NaCl, 4.7 KCl, 27 NaHCO3, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 0.05 EDTA, and 11 mM glucose, plus 300 U heparin). The pH of the perfusate is maintained at 7.4 by gassing the buffer with 95% O2-5% CO2. Each liver is perfused at a flow rate of 20 ml/minutes in a single-pass manner for a 30 minutes washout and equilibration period (preischemic period), followed by a 2 hour period of global ischemia, and then a 2 hour period of reperfusion under conditions identical to the preischemic period. Aliquots (20 ml) of the perfusate are collected during the preischemic period, immediately after the occlusive ischemic period, and every 30 minutes of the 2 hour reperfusion period. The perfusate samples are assayed for the appearance of hepatocellular enzymes, for example, aspartate amino-transferase (AST), alanine amino-transferase (ALT), and lactate dehydrogenase (LDH), which are taken to quantitatively reflect the degree of ischemic liver tissue damage during the procedure. AST, ALT, and LDH activities in the perfusate can be determined by several methods, for example, by the reflectometry method using an automatic Kodak Ektachem 500 analyzer reported by Nakano, et al. (Hepatology 1995;22:539-545). The effect of the compositions and methods of this invention in reducing ischemic liver damage induced by occlusion is noted based on a reduction in the release of hepatocellular enzymes immediately following the occlusive period and/or during the postischemic-reperfusion period in the perfused livers from the rats in the treatment group compared to perfused livers from rats in a placebo-treated control group.
Other methods and parameters which could alternatively be utilized to demonstrate the benefit of the compositions and methods of this invention in reducing ischemic liver damage include those described by Nakano, et al. (Hepatology 1995;22:539-545).
Any glycogen phosphorylase inhibitor may be used as the second compound of this invention. The term glycogen phosphorylase inhibitor refers to any substance or agent or any combination of substances and/or agents which reduces, retards, or eliminates the enzymatic action of glycogen phosphorylase. The currently known enzymatic action of glycogen phosphorylase is the degradation of glycogen by catalysis of the reversible reaction of a glycogen macromolecule and inorganic phosphate to glucose-1-phosphate and a glycogen macromolecule which is one glucosyl residue shorter than the original glycogen macromolecule (forward direction of glycogenolysis). Such actions are readily determined by those skilled in the art according to standard assays (e.g., as described hereinafter). A variety of these, compounds are included in the following published PCT patent applications: PCT application publication WO 96/39384 and WO 96/39385. However, other glycogen phosphorylase inhibitors will be known to those skilled in the art.
Compounds of formula I, prodrugs thereof, mutual prodrugs of the compounds of formula I with aldose reductase inhibitors, pharmaceutically acceptable salts of any of the above and pharmaceutical compositions comprising a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and either (a) an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said aldose reductase inhibitor or said prodrug, (b) a NHE-1 inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrug, or a glycogen phosphorylase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said glycogen phosphorylase inhibitor or said prodrug are hereinafter referred to, collectively, as xe2x80x9cthe active compounds and comopositions of this invention.xe2x80x9d
The active compounds and compositions of this invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, parenterally and topically. In general, compounds of the formula I and their pharmaceutically acceptable salts will be administered orally or parenterally at dosages between about 0.001 and about 100 mg/kg body weight of the subject to be treated per day, preferably from about 0.01 to 10 mg/kg, in single or divided doses. Mutual prodrugs of compounds of the formula I and aldose reductase inhibitors will generally be administered orally or parenterally at dosages between about 0.001 and about 100 mg/kg body weight of the subject to be treated per day, preferably from about 0.01 to about 10 mg/kg, in single or divided doses. Compositions containing both a compound of the formula I and an aldose reductase inhibitor will generally be administered orally or parenterally at dosages between about 0.001 and about 100 mg of each active component (i.e., the compound of formula I and the aldose reductase inhibitor) per kg body weight of the subject to be treated per day, preferably from about 0.01 to about 10 mg/kg. Compositions containing both a compound of formula I and a NHE-1 inhibitor will generally be administered orally or parenterally at dosages between about 0.001 and 100 mg of said compound of formula I per kg body weight of the subject to be treated per day and about 0.001 to 100 mg/kg/day of the NHE-1 inhibitor. An especially preferred dosage contains between about 0.01 and 10 mg/kg/day of said compound of formula I and between about 0.01 and 50 mg/kg/day of said NHE-1 inhibitor. Compositions containing both a compound of formula I and a glcogen phosphorylase inhibitor will generally be administered orally or parenterally at dosages between about 0.001 and 100 mg of said compound of formula I per kg body weight of the subject to be treated per day and 0.005 to 50 mg/kg/day of said glycogen phosphorylase inhibitor, preferably 0.01 and 10 mg/kg/day of said compound of formula and 0.01 to 25 mg/kg/day of said glycogen phosphorylase inhibitor and most preferably 0.01 and 10 mg/kg/day of said compound of formula and 0.1 to 15 mg/kg/day of said glycogen phosphorylase inhibitor. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
The active compounds and compositions of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the active compounds of formula I of this invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
For parenteral administration, solutions of the active compounds and compositions of this invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Administration of the compounds of formula I of this invention can be via any method which delivers a compound of this invention preferentially to the desired tissue (e.g., nerve, kidney, retina and/or cardiac tissues). These methods include oral routes, parenteral, intraduodenal routes, etc. Generally, the compounds of the present invention are administered in single (e.g., once daily) or multiple doses or via constant infusion.
The compositions of this invention comprising a compound of formula I in combination with an NHE-1 inhibitor are useful, for example, in reducing or minimizing damage effected directly to any tissue that may be susceptible to ischemia/reperfusion injury (e.g., heart, brain, lung, kidney, liver, gut, skeletal muscle, retina) as the result of an ischemic event (e.g., myocardial infarction). The composition is therefore usefully employed prophylactically to prevent, i.e. (prospectively or prophylactically) to blunt or stem, tissue damage (e.g., myocardial tissue) in patients who are at risk for ischemia (e.g., myocardial ischemia).
Generally, a compouned of formula I of this invention is administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorders or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician.
The amount and timing of compounds administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgement of the prescribing physician. Thus, because of patient to patient variability, the dosages given below are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.
Thus, for example, in one mode of administration the compounds of formula I of this invention may be administered just prior to surgery (e.g., within twenty-four hours before surgery for example cardiac surgery) during or subsequent to surgery (e.g., within twenty-four hours after surgery) where there is risk of myocardial ischemia. The compounds of formula I of this invention may also be administered in a chronic daily mode.
The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of formula I of this invention together with a pharmaceutically acceptable vehicle or diluent. Thus, the compounds of formula I of this invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form.
For purposes of transdermal (e.g.,topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).
Pharmaceutical compositions according to the invention may contain for example 0.0001%-95% of the compound(s) of this invention. In any event, the composition or formulation to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat the disease/condition of the subject being treated.
The two different compounds of this combination of this invention can be co-administered simultaneously or sequentially in any order, or as a single pharmaceutical composition comprising a compound of Formula I and an aldose reductase inhibitor as described above or a glycogen phosphorylase inhibitor as described above or a cardiovascular agent.
Since the present invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I a prodrug thereof or a salt of such compound or prodrug and a second compound as described above. The kit comprises means for containing the separate compositions such as a container, a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows xe2x80x9cFirst Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . xe2x80x9d etc. Other variations of memory aids will be readily apparent. A xe2x80x9cdaily dosexe2x80x9d can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
The compounds of formula I of this invention generally will be administered in a convenient formulation. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.
In the formulations which follow, xe2x80x9cactive ingredientxe2x80x9d means a compound(s) of this invention.
A tablet for formulation is prepared using the ingredients below:
The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.25-100 mg of active ingredients are made up as follows:
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0-60xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose are made as follows:
The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume. An aerosol solution is prepared containing the following ingredients:
The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30xc2x0 C., and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container. Suppositories are prepared as follows:
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
An intravenous formulation is prepared as follows:
The solution of the above ingredients is intravenously administered to a patient.
The active ingredient above may also be a combination of agents.
Melting points were determined on a Thomas-Hoover capillary melting point apparatus, and are uncorrected. 1H NMR spectra were obtained on a Bruker AM-250 (Bruker Co., Billerica, Mass.), a Bruker AM-300, a Varian XL-300 (Varian Co., Palo Alto, Calif.), or a Varian Unity 400 at about 23xc2x0 C. at 250, 300, or 400 MHz for proton. Chemical shifts are reported in parts per million (xcex4) relative to residual chloroform (7.26 ppm), dimethylsulfoxide (2.49 ppm), or methanol (3.30 ppm) as an internal reference. The peak shapes and descriptors for the peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; c, complex; br, broad; app, apparent. Low-resolution mass spectra were obtained under thermospray (TS) conditions on a Fisons (now Micromass) Trio 1000 Mass Spectrometer (Micromass Inc., Beverly, Mass.), under chemical-ionization (CI) conditions on a Hewlett Packard 5989A Particle Beam Mass Spectrometer (Hewlett Packard Co., Palo Alto, Calif.), or under atmospheric pressure chemical ionization (APCI) on a Fisons (now Micromass) Platform II Spectrometer. Optical rotations were obtained on a Perkin-Elmer 241 MC Polarimeter (Perkin-Elmer, Norwalk, Conn.) using a standard path length of 1 dcm at about 23xc2x0 C. at the indicated concentration in the indicated solvent.
Liquid column chromatography was performed using forced flow (flash chromatography) of the indicated solvent on either Baker Silica Gel (40 xcexcm, J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (EM Sciences, Gibbstown, N.J.) in glass columns or using low nitrogen or air pressure in Flash 40(trademark) or Flash 12(trademark) (Biotage, Charlottesville, Va.) cartridges. Radial chromatography was performed using a Chromatron (Harrison Research, Palo Alto, Calif.). The terms xe2x80x9cconcentratedxe2x80x9d and xe2x80x9cevaporatedxe2x80x9d refer to removal of solvent using a rotary evaporator at water aspirator pressure or at similar pressures generated by a Bxc3xccchi B-171 Vacobox (Brinkmann Instruments, Inc., Westbury, N.Y.) or a Bxc3xcchi B-177 Vacobox with a bath temperature equal to or less than 50xc2x0 C. Reactions requiring the use of hydrogen gas at pressures greater than 1 atmosphere were run using a Parr hydrogen apparatus (Parr Instrument Co., Moline, Ill.). Unless otherwise specified, reagents were obtained from commercial sources. The abbreviations xe2x80x9cdxe2x80x9d, xe2x80x9chxe2x80x9d, and xe2x80x9cminxe2x80x9d stand for xe2x80x9cday(s)xe2x80x9d, xe2x80x9chour(s)xe2x80x9d, and xe2x80x9cminute(s)xe2x80x9d, respectively.